Substituted pyrazolyl benzenesulfonamides for the treatment of gastrointestinal conditions

ABSTRACT

A class of pyrazolyl benzenesulfonamide compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula I: ##STR1## or a pharmaceutically-acceptable salt thereof.

This is a continuation of application Ser. No. 08/223,629 filed Apr. 6,1994, now U.S. Pat. No. 5,521,207 which is a continuation-in part ofapplication Ser. No. 08/160,594, filed Jan. 13, 1994 now U.S. Pat. No.5,466,823.

FIELD OF THE INVENTION

This invention is in the field of anti-inflammatory pharmaceuticalagents and specifically elates to compounds, compositions and methodsfor treating inflammation and inflammation-associated disorders, such asarthritis.

BACKGROUND OF THE INVENTION

Prostaglandins play a major role in the inflammation process and theinhibition of prostaglandin production, especially production of PGG₂,PGH₂ and PGE₂, has been a common target of anti-inflammatory drugdiscovery. However, common non-steroidal anti-inflammatory drugs(NSAIDs) that are active in reducing the prostaglandin-induced pain andswelling associated with the inflammation process are also active inaffecting other prostaglandin-regulated processes not associated withthe inflammation process. Thus, use of high doses of most common NSAIDscan produce severe side effects, including life threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long term therapy is involved.

Pyrazoles have been described for use in the treatment of inflammation.U.S. Pat. No. 5,134,142 to Matsuo et al describes 1,5-diaryl pyrazoles,and specifically, 1-(4-fluorophenyl)-5-4-(methylsulfonyl)phenyl!-3-trifluoromethyl pyrazole, as havinganti-inflammatory activity.

However pyrazolyl-benzenesulfonamides have not been described as havingsuch activity. Certain substituted pyrazolyl-benzenesulfonamides havebeen described in the literature as synthetic intermediates.Specifically, 4-5-(4-chlorophenyl)-3-phenyl-1H-pyrazol1-yl!benzenesulfonamide has beenprepared from a pyrazoline compound as an intermediate for compoundshaving hypoglycemic activity R. Soliman et al, J. Pharm. Sci., 76, 626(1987)!. 4- 5-2-(4-Bromophenyl)-2H-1,2,3-triazol-4-yl!-3-methyl-1H-pyrazol-1-yl!benzenesulfonamidehas been prepared from a pyrazoline compound and described aspotentially having hypoglycemic activity (H. Mokhtar, Pak. J. Sci.Ind.Res., 31, 762 (1988)!.

Similarly, 4- 4-bromo-5-2-(4-chlorophenyl)-2H-1,2,3-triazol-4-yl!-3-methyl-1H-pyrazol-1-yl!benzenesulfonamidehas been prepared H. Mokhtar et al, Pak. J. Sci.Ind. Res., 34, 9(1991)!.

The phytotoxicity of pyrazole derivatives is described M. Cocco et al,Il. Farmaco-Ed. Sci., 40, 272 (1985)!, specifically for 1-4-(aminosulfonyl)phenyl!-5-phenyl-1H-pyrazole-3,4-dicarboxylic acid.

The use of 4- 3,4,5-trisubstituted-pyrazol-1-yl!benzenesulfonamides asintermediates for sulfonylurea anti-diabetes agents is described, andspecifically, 1-4-(aminosulfonyl)phenyl!-3-methyl-5-phenyl-1H-pyrazole-4-carboxylic acidR. Soliman et al, J. Pharm, Sci., 72, 1004 (1983)!. A series of 4-3-substitutedmethyl-5phenyl-1H-pyrazol-1-yl!benzenesulfonamides has beenprepared as intermediates for anti-diabetes agents, and morespecifically, 4- 3-methyl-5-phenyl-1H-pyrazol-1-yl!benzenesulfonamide H.Feid-Allah, Pharmazie, 36, 754 (1981)!. In addition, 1-(4-aminosulfonyl!phenyl)-5-phenylpyrazole-3-carboxylic acid has beenprepared from the above described 4-3-methyl-5-phenyl-1H-pyrazol-1-yl!benzenesulfonamide compound R. Solimanet al, J. Pharm. Sci., 70, 602 (1981)!.

DESCRIPTION OF THE INVENTION

A class of compounds useful in treating inflammation-related disordersis defined by Formula I: ##STR2## wherein R¹ is selected from sulfamyl,halo, alkyl, alkoxy, hydroxyl and haloalkyl; wherein R² is selected fromhydrido, halo, haloalkyl, cyano, nitro, formyl, carboxyl,alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino,cyanoamidino, amido, alkoxy, amidoalkyl, N-monoalkylamido,N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, alkylcarbonyl,alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl,alkylsulfonyl, N-alkylsulfamyl, N-arylsulfamyl, arylsulfonyl,N,N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl and heterocyclic; wherein R³is selected from hydrido, halo, alkyl, haloalkyl, cyano, nitro, formyl,carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino,cyanoamidino, amido, alkoxy, amidoalkyl, N-monoalkylamido,N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, alkylcarbonyl,alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl,alkylsulfonyl, N-alkylsulfamyl, N-arylsulfamyl, arylsulfonyl,N,N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl, heterocyclic,heterocycloalkyl and aralkyl; wherein R⁴ is selected from aryl,cycloalkyl, cycloalkenyl and heterocyclic; wherein R⁴ is optionallysubstituted at a substitutable position with one or more radicalsselected from halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl,cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido,N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl,hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl,amino, N-alkylamino, N,N-dialkylamino, heterocyclic, nitro andacylamino; or wherein R³ and R⁴ together form ##STR3## and m is 1 to 3,inclusive; and wherein R⁵ is one or more radicals selected from halo,alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, carboxyl,alkoxycarbonyl, amido, N-monoalkylamido, N-monoarylamido, alkyl,N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydrido, hydroxyl,alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino,alkylamino, heterocyclic, nitro and acylamino; provided R² and R³ arenot identical radicals selected from hydrido, carboxyl andethoxycarbonyl; further provided that R² cannot be carboxyl when R³ ishydrido and when R⁴ is phenyl; and further provided that R⁴ is sulfamylor N-alkylsulfamyl when R¹ is halo; or a pharmaceutically-acceptablesalt thereof.

The phrase "further provided", as used in the above description, isintended to mean that the denoted proviso is not to be consideredconjunctive with any of the other provisos.

Compounds of Formula I would be useful for the treatment of inflammationin a subject, and for treatment of other inflammation-associateddisorders, such as an analgesic in the treatment of pain and headaches,or as an antipyretic for the treatment of fever. For example, compoundsof Formula I would be useful to treat arthritis, including but notlimited to rheumatoid arthritis, spondyloarthopathies, gouty arthritis,systemic lupus erythematosus, osteoarthritis and juvenile arthritis.Such compounds of Formula I would be useful in the treatment of asthma,bronchitis, menstrual cramps, tendinitis, bursitis, and skin relatedconditions such as psoriasis, eczema, burns and dermatitis. Compounds ofFormula I also would be useful to treat gastrointestinal conditions suchas inflammatory bowel syndrome, Crohn's disease, gastritis, irritablebowel syndrome and ulcerative colitis. Compounds of Formula I would beuseful in treating inflammation in such diseases as vascular diseases,migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia,Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes,myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, hypersensitivity, conjunctivitis, gingivitis, swellingoccurring after injury, myocardial ischemia, and the like. The compoundsare useful as anti-inflammatory agents, such as for the treatment ofarthritis, with the additional benefit of having significantly lessharmful side effects.

A preferred class of compounds consists of those compounds of Formula Iwherein R² is selected from halo, haloalkyl, cyano, nitro, formyl,carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino,cyanoamidino, amido, amidoalkyl, N-monoalkylamido, N-monoarylamido,N,N-dialkylamido, N-alkyl-N-arylamido, alkylcarbonyl,alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl,alkylsulfonyl, N-alkylsulfamyl, N-arylsulfamyl, arylsulfonyl,N,N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl and heterocyclic; wherein R³is hydrido; wherein R⁴ is selected from aryl, cycloalkyl, cycloalkenyland heterocyclic; wherein R⁴ is optionally substituted at asubstitutable position with one or more radicals selected from halo,alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl,alkoxycarbonyl, amido, N-monoalkylamido, N-monoarylamido,N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy,hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino,N-alkylamino, N,N-dialkylamino, heterocyclic, nitro and acylamino; orwherein R³ and R⁴ together form ##STR4## and m is 1 to 3, inclusive; andwherein R⁵ is one or more radicals selected from halo, alkylthio,alkylsulfinyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido,N-monoalkylamido, N-monoarylamido, alkyl, N,N-dialkylamido,N-alkyl-N-arylamido, haloalkyl, hydrido, hydroxyl, alkoxy, hydroxyalkyl,haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, alkylamino, heterocyclic,nitro and acylamino; or a pharmaceutically-acceptable salt thereof.

A second preferred class of compounds consists of those compounds ofFormula I wherein R¹ is sulfamyl; and wherein R³ is hydrido; or apharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula I wherein R¹ is sulfamyl; wherein R² is selected from fluoro,chloro, bromo, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, cyano,nitro, formyl, carboxyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, tertbutoxycarbonyl, propoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, pentoxycarbonyl, amido, N-methylamido, N-ethylamido,N-isopropylamido, N-propylamido, N-butylamido, N-isobutylamido,N-tert-butylamido, N-pentylamido, N-cyclohexylamido, N-cyclopentylamido,N,N-dimethylamido, N-methyl-N-ethylamido, pyrrolidinoamido,piperidinoamido, N-phenylamido, N-(3-fluorophenyl)amido,N-(4-methylphenyl)amido, N-(3-chlorophenyl)amido,N-(4-methoxyphenyl)amido, 2-pyridylamido, N-methyl-N-phenylamido,N-methyl-N-pyridylamido, methylsulfonyl, phenylsulfonyl,N-phenylsulfamyl, N-methylsulfamyl, N-ethylsulfamyl,N-isopropylsulfamyl, N,N-dimethylsulfamyl, N-methyl-N-ethylsulfamyl,N-methyl-N-(3-chlorophenyl)sulfamyl, N-methyl-N-(2-pyridyl)sulfamyl,amidino, cyanoamidino, hydroxypropyl, hydroxymethyl, hydroxyethyl,carboxypropyl, carboxymethyl, carboxyethyl, tetrazolyl, imidazolyl andpyridyl; wherein R³ is hydrido; wherein R⁴ is selected from phenyl,naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl,1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl,4-methylcyclohex-4-ene-1-yl, 1-cyclopentenyl, pyridyl, thienyl,thiazolyl, oxazolyl, furyl and pyrazinyl; wherein R⁴ is optionallysubstituted at a substitutable position with one or more radicalsselected from fluoro, chloro, bromo, methylthio, methylsulfinyl, cyano,carboxyl, amido, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,tertbutoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,pentoxycarbonyl, N-methylamido, N-ethylamido, N-isopropylamido,N-propylamido, N-butylamido, N-isobutylamido, N-tert-butylamido,N-pentylamido, N-cyclohexylamido, N-cyclopentylamido, N,N-dimethylamido,N-methyl-N-ethylamido, pyrrolidinoamido, piperidinoamido, N-phenylamido,N-(3-fluorophenyl)amido, N-(4-methylphenyl)amido,N-(3-chlorophenyl)amido, N-(4methoxyphenyl)amido, 2-pyridylamido,N-methyl-N-phenylamido, N-methyl-N-pyridylamido, methyl, ethyl,isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy,n-butoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl,sulfamyl, methylsulfamyl, amino, nitro, methylamino, dimethylamino,formylamino, acetamino, trifluoroacetamino and morpholino; or apharmaceutically-acceptable salt thereof.

A family of specific compounds of particular interest within Formula Iconsists of compounds and pharmaceutically-acceptable salts thereof asfollows:

4-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1yl!benzenesulfonamide;

4-5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-bromophenyl)-3-(cyano)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-nitrophenyl)-3-(cyano)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

1- 4-(aminosulfonyl)phenyl!-5-(4-bromophenyl)-1H-pyrazole-3-carboxamide;

4-5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

methyl-1-4-(aminosulfonyl)phenyl!-5-(4-aminophenyl)-1H-pyrazole-3-carboxylate;

4-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

ethyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

1- 4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid;

4-5-(2-pyrazinyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

4- 5-(4-methylthio!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-methylsulfonyl!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(2,4-difluoro!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(2,6-difluoro!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(5-chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-(morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(1-cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(5-bromo-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-trifluoromethyl!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;

4-5-(3,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1-yl!benzenesulfonamide;

N-phenyl-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N-(4-methoxyphenyl)-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N-(3-fluorophenyl)-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N-(3-chlorophenyl)-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-(4-methylphenyl)-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

4-5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl!benzenesulfonamide;

1- 4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole-3-propanoicacid;

methyl-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole-3-propanoate;

4- 5-(4-chlorophenyl)-3-(chloro)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-chlorophenyl)-3-(bromo)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-chlorophenyl)-3-(fluoro)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(fluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(chloromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(dichloromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

methyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

4- 5-(4-chlorophenyl)-3-(cyano)-1H-pyrazol-1-yl!benzenesulfonamide;

N,N-dimethyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-N-ethyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-phenyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-N-phenyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

4- 5-(4-chlorophenyl)-3-(dichlorofluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-chlorophenyl)-3-(nitro)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-chlorophenyl)-3-(amidino)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(methylsulfonyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(N-methyl-aminosulfonyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,4,6-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,6-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,4,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3,5-dimethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-methoxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3,4-dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3,4-dimethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3,4-methylenedioxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-fluoro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:

4-5-(2-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-fluoro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-chloro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chloro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3,4-dihydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(biphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(5-indanyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(5-2,3-dihydrobenzofuranyl!)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(6-1,2,3,4-tetrahydronapthyl!)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-ethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(6-methoxy-2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-N-methylaminolphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-N,N-dimethylamino!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-N-formylaminolphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-N-acetylamino!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-N-methylaminosulfonyl!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-hydroxymethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(5-chloro-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-thiazolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-oxazolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(cyclohexyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(cyclopentyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(cycloheptyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(1-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(1-cyclopentenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1yl!benzenesulfonamide;

4-5-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-ethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-n-butoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-aminosulfonyl!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(2-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(3-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(6-methyl-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-acetamidophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-N-trifluoroacetamido!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-fluorophenyl)-3-(imidazolyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-fluorophenyl)-3-(trichloromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-fluorophenyl)-3-(2-pyridyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 1-4-(aminosulfonyl)phenyl!-3-(trifluoromethyl)-1H-pyrazol-5-yl!benzoicacid;

methyl-4- 1-4-(aminosulfonyl)phenyl!-3-(trifluoromethyl)-1H-pyrazol-5-yl!benzoate;

4- 1-4-(aminosulfonyl)phenyl!-3-(trifluoromethyl)-1H-pyrazol-5-yl!benzamide;

1-4-(aminosulfonyl)phenyl!-5-(4-flourophenyl)-1H-pyrazol-1-yl!-3-propanoicacid;

ethyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

isopropyl-1-(4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

tert-butyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

propyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

butyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

isobutyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

pentyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

N-ethyl-1-4-(aminosulfonyl)phenyl!-5(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-isopropyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-propyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-butyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-isobutyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-tert-butyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-pentyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-cyclohexyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-cyclopentyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

4-5-(4-chlorophenyl)-3-(pyrrolidinocarboxamide)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(piperidinocarboxamide)-1H-pyrazol-1-yl!benzenesulfonamide;

N-(3-chlorophenyl)-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-(2-pyridyl)-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-N-(3-chlorophenyl)-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3carboxamide;

4-5-(4-chlorophenyl)-3-(1,1-difluoroethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(1,1-difluoropropyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(1,1-dichloroethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(1,1-dichloropropyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(N-cyanoamidino)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-chlorophenyl)-3-(tetrazolyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(phenylsufonyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(N-phenylaminosulfonyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(N,N-dimethylaminosulfonyl)1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(N-methyl-N-phenylaminosulfonyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(N-ethylaminosulfonyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(N-isopropylaminosulfonyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(N-methyl-N-ethylaminosulfonyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(N-methyl-N-(3-chlorophenyl)aminosulfonyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(N-methyl-N-(2-pyridyl)aminosulfonyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,3,4-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3,4,5-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,4,5-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,5,6-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,3,4,5-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,3,4,6-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,3,5,6-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(pentafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,3,4-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,4,5-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,5,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,3,4,5-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,3,4,6-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,3,5,6-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(pentachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-tertbutylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-isobutylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-methylcyclohex-4-ene-1-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(5-chloro-2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;and

4-5-(5-bromo-2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide.

A third preferred class of compounds consists of those compounds ofFormula I wherein R¹ is sulfamyl; wherein R³ and R⁴ together form##STR5##

and m is 1 to 3, inclusive; and wherein R⁵ is one or more radicalsselected from halo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano,carboxyl, alkoxycarbonyl, amido, N-monoalkylamido, N-monoarylamido,alkyl, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydroxyl,alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino,alkylamino, heterocyclic, nitro and acylamino; or apharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula I wherein R¹ is sulfamyl; wherein R² is selected from fluoro,chloro, bromo, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, cyano,nitro, formyl, carboxyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, tertbutoxycarbonyl, propoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, pentoxycarbonyl, amido, N-methylamido, N-ethylamido,N-isopropylamido, N-propylamido, N-butylamido, N-isobutylamido,N-tert-butylamido, N-pentylamido, N-cyclohexylamido, N-cyclopentylamido,N,N-dimethylamido, N-methyl-N-ethylamido, pyrrolidinoamido,piperidinoamido, N-phenylamido, N-(3-fluorophenyl)amido,N-(4-methylphenyl)amido, N-(3-chlorophenyl)amido,N-(4-methoxyphenyl)amido, 2-pyridylamido, N-methyl-N-phenylamido,N-methyl-N-pyridylamido, methylsulfonyl, phenylsulfonyl,N-phenylsulfamyl, N-methylsulfamyl, N-ethylsulfamyl,N-isopropylsulfamyl, N,N-dimethylsulfamyl, N-methyl-N-ethylsulfamyl,N-methyl-N-(3chlorophenyl)sulfamyl, N-methyl-N-(2-pyridyl)sulfamyl,amidino, cyanoamidino, hydroxypropyl, hydroxymethyl, hydroxyethyl,carboxypropyl, carboxymethyl, carboxyethyl, tetrazolyl, imidazolyl andpyridyl; wherein R³ and R⁴ together form ##STR6## and m is 1 to 3,inclusive; and wherein R⁵ is one or more radicals selected from fluoro,chloro, bromo, methylthio, methylsulfinyl, cyano, carboxyl, amido,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tertbutoxycarbonyl,propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl,N-methylamido, N-ethylamido, N-isopropylamido, N-propylamido,N-butylamido, N-isobutylamido, N-tertbutylamido, N-pentylamido,N-cyclohexylamido, N-cyclopentylamido, N,N-dimethylamido,N-methyl-N-ethylamido, pyrrolidinoamido, piperidinoamido, N-phenylamido,N-(3-fluorophenyl)amido, N-(4methylphenyl)amido,N-(3-chlorophenyl)amido, N-(4methoxyphenyl)amido, 2-pyridylamido,N-methyl-N-phenylamido, N-methyl-N-pyridylamido, methyl, ethyl,isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyi, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy,n-butoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl,sulfamyl, methylsulfamyl, amino, nitro, methylamino, dimethylamino,formylamino, acetamino, trifluoroacetamino and morpholino; or apharmaceutically-acceptable salt thereof.

A fourth preferred class of compounds consists of those compounds ofFormula I wherein R¹ is selected from halo, alkyl, alkoxy, hydroxyl andhaloalkyl; wherein R² is selected from haloalkyl; and wherein R⁴ isphenyl substituted at a substitutable position with sulfamyl; or apharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula I wherein R¹ is selected from fluoro, chloro, bromo,fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichloropropyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl, methyl, ethyl, propyl,hydroxyl, methoxy, ethoxy, propoxy and n-butoxy; wherein R² is selectedfrom fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, difluoroethyl, dichlorofluoromethyl,difluoropropyl, dichloroethyl and dichloropropyl; and wherein R³ ishydrido; or a pharmaceutically-acceptable-salt thereof.

A specific compound of particular interest within Formula I is 4-l-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl!benzenesulfonamide,or a pharmaceutically-acceptable salt thereof.

Within Formula I there is a fifth preferred class of compounds whichconsists of compounds wherein R¹ is sulfamyl; wherein R² is selectedfrom hydrido, halo, haloalkyl, cyano, nitro, formyl, carboxyl,alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino,cyanoamidino, amido, alkoxy, amidoalkyl, N-monoalkylamido,N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, alkylcarbonyl,alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl,alkylsulfonyl, N-alkylsulfamyl, N-arylsulfamyl, arylsulfonyl,N,N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl and heterocyclic; wherein R³is selected from halo, haloalkyl, cyano, nitro, formyl, carboxyl,alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino,cyanoamidino, amido, alkoxy, amidoalkyl, N-monoalkylamido,N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, alkylcarbonyl,alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkyl, alkylsulfinyl,alkylsulfonyl, N-alkylsulfamyl, N-arylsulfamyl, arylsulfonyl,N,N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl, heterocyclic,heterocycloalkyl and aralkyl; wherein R⁴ is selected from aryl,cycloalkyl, cycloalkenyl and heterocyclic; wherein R⁴ is optionallysubstituted at a substitutable position with one or more radicalsselected from halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl,cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido,N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl,hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl,amino, N-alkylamino, N,N-dialkylamino, heterocyclic, nitro andacylamino; or a pharmaceutically-acceptable salt thereof.

An even more preferred class contains compounds wherein R² is hydrido orhaloalkyl; wherein R³ is selected from alkyl, halo, carboxyalkyl,N-monoalkyl-N-hydroxyamido, N-monoalkyl-N-hydroxyamidoalkyl andN-monoalkylamido; and wherein R⁴ is aryl optionally substituted at asubstitutable position with halo; or a pharmaceutically-acceptable saltthereof.

A class of compounds of particular interest consist of those compoundswherein R¹ is sulfamyl; wherein R² is selected from hydrido,fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl; wherein R³ is selectedfrom fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl,N-methylamido, N-ethylamido, N-isopropylamido, N-propylamido,N-butylamido, N-isobutylamido, N-tert-butylamido, N-pentylamido,N-cyclohexylamido, N-cyclopentylamido, carboxypropyl, carboxymethyl,carboxyethyl, N-methyl-N-hydroxyamido, N-methyl-N-hydroxyamidomethyl,N-methyl-N-hydroxyamidoethyl and N-methyl-N-hydroxyamidopropyl; andwherein R⁴ is phenyl optionally substituted at a substitutable positionwith one or more radicals selected from fluoro, chloro and bromo; or apharmaceutically-acceptable salt thereof.

A family of specific compounds of particular interest consists ofcompounds and their pharmaceutically acceptable salts thereof asfollows:

4-5-(4-chlorophenyl)-3-(trifluoromethyl)-4-(methyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(trifluoromethyl)-4-fluoro-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-chlorophenyl)-4-fluoro-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-fluorophenyl)-3-(trifluoromethyl)-4-(n-propyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-chlorophenyl)-4-chloro-1H-pyrazol-1-yl!benzenesulfonamide;

N-methyl-N-hydroxy-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-ethanamide;

4-5-(4-fluorophenyl)-3-(trifluoromethyl)-4-(phenylethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-fluorophenyl)-3-(trifluoromethyl)-4-(2-2-pyridyl!ethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-fluorophenyl)-3-(trifluoromethyl)-4-(N,N-dimethylamino!ethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-3-chloro-1H-pyrazole-4-aceticacid;

1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-propanoicacid;

methyl-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-propanoate;

1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-propanamide;

N-methyl-N-hydroxy-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4propanamide;

N-methyl-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;and

4-5-(4-fluorophenyl)-3-(trifluoromethyl)-4-(methyl)-1H-pyrazol-1-yl!benzenesulfonamide.

Within Formula I there is a subclass of compounds of high interestrepresented by Formula II: ##STR7## wherein R² is selected from hydrido,haloalkyl, alkoxycarbonyl, cyano, amido, arylamido, carboxyalkyl andhydroxyalkyl; wherein R³ is hydrido or halo; and wherein R⁴ is selectedfrom aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R⁴ isoptionally substituted at a substitutable position with one or moreradicals selected from halo, alkylthio, alkylsulfonyl, cyano, nitro,haloalkyl, alkyl, hydrido, alkoxy, haloalkoxy, sulfamyl, heterocyclicand amino; or wherein R³ and R⁴ together form ##STR8## provided R² andR³ are not both hydrido; or a pharmaceutically-acceptable salt thereof.

A preferred class of compounds consists of those compounds of Formula IIwherein R² is selected from hydrido, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, cyano, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, tertbutoxycarbonyl, propoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, pentoxycarbonyl, amido, N-phenylamido,N-(3-fluorophenyl)amido, N-(4-methylphenyl)amido,N-(3-chlorophenyl)amido, N-(4-methoxyphenyl)amido, 2-pyridylamido,hydroxypropyl, hydroxymethyl, hydroxyethyl, carboxypropyl, carboxymethyland carboxyethyl; wherein R³ is selected from hydrido, fluoro, chloro,iodo and bromo; wherein R⁴ is selected from phenyl, biphenyl, pyrazinyl,cyclohexyl, cyclohexenyl and thienyl; and wherein R⁴ is optionallysubstituted at a substitutable position with one or more radicalsselected from chloro, bromo, fluoro, methylthio, methylsulfonyl,morpholinyl, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl,methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy,fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl; or wherein R³ and R⁴together form ##STR9## or a pharmaceutically-acceptable salt thereof.

A family of specific compounds of particular interest within Formula IIconsists of compounds and pharmaceutically-acceptable salts thereof asfollows:

4-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-chlorophenyl)-4-chloro-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-bromophenyl)-3-(cyano)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-nitrophenyl)-3-(cyano)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

1- 4-(aminosulfonyl)phenyl!-5-(4-bromophenyl)-1H-pyrazole-3-carboxamide;

4-5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

methyl-1-4-(aminosulfonyl)phenyl!-5-(4-aminophenyl)-1H-pyrazole-3-carboxylate;

4-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

ethyl-1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

1-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

4- 5-(4-methylthio!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(2,4-difluoro!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(2,6-difluoro!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(5-chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(4-(morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol1-yl!benzenesulfonamide;

4-5-(l-cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(5-bromo-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-(4-trifluoromethyl!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(2,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4- 5-phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1yl!benzenesulfonamide;

N-phenyl-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N- 4-methoxyphenyl!-1-4-(aminosulfonyl)phenyl!-5(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N- 3-fluorophenyl!-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N- 3-chlorophenyl!-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N- 4-methylphenyl!-1-4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

4- 4,5-dihydro-3-(trifluoromethyl)-1H-benzg!indazol-1-yl!benzenesulfonamide;

4-5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl!benzenesulfonamide;

4-5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;and

1- 4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole-3-propanoicacid.

Where the term "alkyl" is used, either alone or within other terms suchas "haloalkyl" and "alkylsulfonyl", it embraces linear or branchedradicals having one to about twenty carbon atoms or, preferably, one toabout twelve carbon atoms. More preferred alkyl radicals are "loweralkyl" radicals having one to about ten carbon atoms. Most preferred arelower alkyl radicals having one to about five carbon atoms. Examples ofsuch radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and thelike. The term "hydrido" denotes a single hydrogen atom (H). Thishydrido radical may be attached, for example, to an oxygen atom to forma hydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (--CH₂ --) radical. The term "halo" meanshalogens such as fluorine, chlorine, bromine or iodine atoms. The term"haloalkyl" embraces radicals wherein any one or more of the alkylcarbon atoms is substituted with halo as defined above. Specificallyembraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. Amonohaloalkyl radical, for one example, may have either a bromo, chloroor a fluoro atom within the radical. Dihalo radicals may have two ormore of the same halo atoms or a combination of different halo radicalsand polyhaloalkyl radicals may have more than two of the same halo atomsor a combination of different halo radicals. The term "hydroxyalkyl",embraces linear or branched alkyl radicals having one to about tencarbon atoms any one of which may be substituted with one or morehydroxyl radicals. The terms "alkoxyl" and "alkoxyalkyl" embrace linearor branched oxy-containing radicals each having alkyl portions of one toabout ten carbon atoms, such as methoxy radical. The term "alkoxyalkyl"also embraces alkyl radicals having two or more alkoxy radicals attachedto the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylradicals. The "alkoxy" or "alkoxyalkyl" radicals may be furthersubstituted with one or more halo atoms, such as fluoro, chloro orbromo, to provide "haloalkoxy" or "haloalkoxyalkyl" radicals. Examplesof "alkoxy" radicals include methoxy, butoxy and trifluoromethoxy. Theterm "aryl", alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term "aryl"embraces aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl,indane and biphenyl. The term "heterocyclic" embraces saturated,partially saturated and unsaturated heteroatom-containing ring-shapedradicals, where the heteroatoms may be selected from nitrogen, sulfurand oxygen. Examples of saturated heterocyclic radicals includepyrrolidyl and morpholinyl. The term "heteroaryl" embraces unsaturatedheterocyclic radicals. Examples of unsaturated heterocyclic radicals,also termed "heteroaryl" radicals include thienyl, pyrryl, furyl,pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl,imidazolyl, thiazolyl, pyranyl and tetrazolyl. The term also embracesradicals where heterocyclic radicals are fused with aryl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like. The term "sulfonyl", whether used alone orlinked to other terms such as alkylsulfonyl, denotes respectivelydivalent radicals --SO₂ --. "Alkylsulfonyl", embraces alkyl radicalsattached to a sulfonyl radical, where alkyl is defined as above. Theterm "arylsulfonyl" embraces sulfonyl radicals substituted with an arylradical. The terms "sulfamyl" or "sulfonamidyl", whether alone or usedwith terms such as "N-alkylsulfamyl", "N-arylsulfamyl","N,N-dialkylsulfamyl" and "N-alkyl-N-arylsulfamyl", denotes a sulfonylradical substituted with an amine radical, forming a sulfonamide (--SO₂NH₂). The terms "N-alkylsulfamyl" and "N,N-dialkylsulfamyl" denotesulfamyl radicals substituted, respectively, with one alkyl radical, acycloalkyl ring, or two alkyl radicals. The terms "N-arylsulfamyl" and"N-alkyl-N-arylsulfamyl" denote sulfamyl radicals substituted,respectively, with one aryl radical, and one alkyl and one aryl radical.The terms "carboxy" or "carboxyl", whether used alone or with otherterms, such as "carboxyalkyl", denotes --CO₂ H. The term "carboxyalkyl"embraces radicals having a carboxy radical as defined above, attached toan alkyl radical. The term "carbonyl", whether used alone or with otherterms, such as "alkylcarbonyl", denotes --(C═O)--. The term"alkylcarbonyl" embraces radicals having a carbonyl radical substitutedwith an alkyl radical. An example of an "alkylcarbonyl" radical is CH₃--(C═O)--. The term "alkylcarbonylalkyl", denotes an alkyl radicalsubstituted with an "alkylcarbonyl" radical. The term "alkoxycarbonyl"means a radical containing an alkoxy radical, as defined above, attachedvia an oxygen atom to a carbonyl (C═O) radical. Examples of such"alkoxycarbonyl" radicals include (CH₃)₃ CO--C(═O)-- and --(O═)C--OCH₃.The term "alkoxycarbonylalkyl" embraces radicals having"alkoxycarbonyl", as defined above substituted to an alkyl radical.Examples of such "alkoxycarbonylalkyl", radicals include (CH₃)₃COC(═O)(CH₂)₂ -- and --(CH₂)₂ (═O)COCH₃. The term "amido" when used byitself or with other terms such as "amidoalkyl", "N-monoalkylamido","N-monoarylamido", "N,N-dialkylamido", "N-alkyl-N-arylamido","N-alkyl-N-hydroxyamido" and "N-alkyl-N-hydroxyamidoalkyl", embraces acarbonyl radical substituted with an amino radical. The terms"N-alkylamido" and "N,N-dialkylamido" denote amido groups which havebeen substituted with one alkyl radical and with two alkyl radicals,respectively. The terms "N-monoarylamido" and "N-alkyl-N-arylamido"denote amido radicals substituted, respectively, with one aryl radical,and one alkyl and one aryl radical. The term "N-alkyl-N-hydroxyamido"embraces amido radicals substituted with a hydroxyl radical and with analkyl radical. The term "N-alkyl-N-hydroxyamidoalkyl" embraces alkylradicals substituted with an N-alkyl-N-hydroxyamido radical. The term"amidoalkyl" embraces alkyl radicals substituted with amido radicals.The term "aminoalkyl" embraces alkyl radicals substituted with aminoradicals. The term "alkylaminoalkyl" embraces aminoalkyl radicals havingthe nitrogen atom substituted with an alkyl radical. The term "amidino"denotes an --C(═NH)--NH₂ radical. The term "cyanoamidino" denotes an--C(═N--CN)--NH₂ radical. The term "heterocycloalkyl" embracesheterocyclic-substituted alkyl radicals such as pyridylmethyl andthienylmethyl. The term "aralkyl" embraces aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, anddiphenethyl. The terms benzyl and phenylmethyl are interchangeable. Theterm "cycloalkyl" embraces radicals having three to ten carbon atoms,such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.The term "cycloalkenyl" embraces unsaturated radicals having three toten carbon atoms, such as cylopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl and cycloheptenyl. The term "alkylthio" embraces radicalscontaining a linear or branched alkyl radical, of one to ten carbonatoms, attached to a divalent sulfur atom. An example of "alkylthio" ismethylthio, (CH₃ --S--). The term "alkylsulfinyl" embraces radicalscontaining a linear or branched alkyl radical, of one to ten carbonatoms, attached to a divalent --S(═O)-- atom. The terms "N-alkylamino"and "N,N-dialkylamino" denote amino groups which have been substitutedwith one alkyl radical and with two alkyl radicals, respectively. Theterm "acyl", whether used alone, or within a term such as "acylamino",denotes a radical provided by the residue after removal of hydroxyl froman organic acid. The term "acylamino" embraces an amino radicalsubstituted with an acyl group. An examples of an "acylamino" radical isacetylamino (CH₃ C(═O)--NH--).

The present invention comprises a pharmaceutical composition for thetreatment of inflammation and inflammation-associated disorders, such asarthritis, comprising a therapeutically-effective amount of a compoundof Formula I in association with at least onepharmaceutically-acceptable carrier, adjuvant or diluent.

The present invention also comprises a therapeutic method of treatinginflammation or inflammation-associated disorders in a subject, themethod comprising administering to a subject having such inflammation ordisorder a therapeutically-effective amount of a compound of Formula I.

Also included in the family of compounds of Formula I are thepharmaceutically-acceptable salts thereof. The term"pharmaceutically-acceptable salts" embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic,salicyclic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, b-hydroxybutyric, salicyclic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formula I include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from N,N'-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. All of these salts may be prepared byconventional means from the corresponding compound of Formula I byreacting, for example, the appropriate acid or base with the compound ofFormula I.

GENERAL SYNTHETIC PROCEDURES

The compounds of the invention can be synthesized according to thefollowing procedures of Schemes I-IV, wherein the R¹ -R⁵ substituentsare as defined for Formula I, above, except where further noted.Synthetic Scheme I shows the preparation of tetrasubstituted pyrazolesfrom starting material 1. In step 1 of synthetic Scheme I, thephenyl-methyl ketone (1) is treated with a base (preferably a lithiumbase such as lithium diisopropylamide or LiHMDS) and an alkylatingreagent (R³ X, where x represents a leaving group such as tosyl) to givethe substituted ketone (2). In step 2, the substituted ketone (2) istreated with base, such as sodium methoxide, and an ester, or esterequivalent, to give the intermediate diketone (3) in a procedure similarto that developed by Reid and Calvin, J. Amer. Chem. Soc., 72, 2948-2952(1950). In step 3, the diketone (3) is reacted with a substitutedphenylhydrazine in acetic acid or an alcoholic solvent to give a mixtureof pyrazoles (4) and (5). Separation of the desired pyrazole (4) can beachieved by chromatography or recrystallization. ##STR10##

Synthetic Scheme II shows the preparation of compounds embraced byFormula I, where R³ is a hydrogen atom. In step 1, ketone (1) is treatedwith a base, preferably NaOMe or NaH, and an ester, or ester equivalent,to form the intermediate diketone (6) which is used without furtherpurification. In step 2, diketone (6) in an anhydrous protic solvent,such as absolute ethanol or acetic acid, is treated with thehydrochloride salt or the free base of a phenylhydrazine at reflux for10 to 24 hours to afford a mixture of pyrazoles (7) and (8).Recrystallization from diethyl ether/hexane or chromatography affords(7), usually as a light yellow or tan solid. ##STR11##

Synthetic Scheme III shows the procedure for preparation of4,5-dihydrobenz g!indazole compounds embraced by Formula I. In step 1,ethyl trifluoroacetate is reacted with base, such as 25% sodiummethoxide in a protic solvent, such as methanol, and a 1-tetralonederivative (9) to give the intermediate diketone (10). In step 2, thediketone (10) in an anhydrous protic solvent, such as absolute ethanolor acetic acid, is treated with the free base or hydrochloride salt of aphenylhydrazine at reflux for 24 hours to afford a mixture of pyrazoles(11) and (12). Recrystallization gives the 4,5-dihydro benzg!indazolyl-benzenesulfonamide (11). ##STR12##

Synthetic Scheme IV shows the preparation of pyrazole compounds (13),where R³ is chlorine, from the available pyrazole compounds (7), whereR³ is hydrogen. Chlorination results from passing a stream of chlorinegas at room temperature through a solution containing (7). ##STR13##

The following examples contain detailed descriptions of the methods ofpreparation of compounds of Formula I-II. These detailed descriptionsfall within the scope, and serve to exemplify, the above describedGeneral Synthetic Procedures which form part of the invention. Thesedetailed descriptions are presented for illustrative purposes only andare not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated.

EXAMPLE 1 ##STR14## 4-5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4,4-trifluoro-1-4(chloro)phenyl!-butane-1,3-dione.

Ethyl trifluoroacetate (23.52 g, 166 mmol) was placed in a 500 mLthree-necked round bottom flask, and dissolved in methyl tert-butylether (75 mL). To the stirred solution was added 25 weight % sodiummethoxide (40 mL, 177 mmol) via an addition funnel over a 2 minuteperiod. Next 4'-chloroacetophenone (23.21 g, 150 mmol) was dissolved inmethyl tert-butyl ether (20 mL), and added to the reaction dropwise over5 minutes. After stirring overnight (15.75 hours), 3N HCl (70 mL) wasadded. The organic layer was collected, washed with brine (75 mL), driedover MgSO₄, filtered, and concentrated in vacuo to give a 35.09 g ofyellow-orange solid. The solid was recrystallized from iso-octane togive 31.96 g, 85% of the dione, mp 66°-67° C.

Step 2: Preparation of 4-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1yl!benzenesulfonamide.

4-Sulphonamidophenyl hydrazine hydrochloride (982 mg, 4.4 mmol 1.1equivalent) was added to a stirred solution of 4,4,4-trifluoro-1-4-(chloro)phenyl!-butane-1,3-dione (1.00 g, 4.0 mmol) in ethanol (50mL). The reaction was heated to reflux and stirred for 20 hours. (HPLCarea percent showed a 96:3 ratio of 4-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamideto its regioisomer (4-3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide).After cooling to room temperature, the reaction mixture was concentratedin vacuo. The residue was taken up in ethyl acetate and washed withwater and brine and dried over MgSO₄, filtered, and concentrated invacuo to give a light brown solid which was recrystallized from ethylacetate and iso-octane to give the pyrazole 2, 1.28 g, 80% yield, mp143°-145° C. HPLC showed that the purified material was a 99.5:0.5mixture of 4-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamideto its regioisomer. ¹ H NMR (CDCl₃ /CD₃ OD 10/1) d 5.2 (s, 2H), 6.8 (s,1H), 7.16 (d, j=8.5 Hz, 2H), 7.35 (d, j=8.5 Hz, 2H), 7.44 (d, j=8.66,2H), 7.91 (d, j=8.66, 2H); ¹³ C NMR (CDCl₃ /CD₃ OD 10/1) d 106.42 (d,j=0.03 Hz), 121.0 (q, j=276 Hz), 125.5, 126.9, 127.3, 129.2, 130.1,135.7, 141.5, 143.0, 143.9 (q, j=37 Hz), 144.0; ¹⁹ F NMR (CDCl₃ /CD₃ OD10/1) d -62.9. EI GC-MS M+=401.

The following compounds (Examples 1a to 1j) were obtained according toprocedures similar to that exemplified in Example 1, with thesubstitution of the appropriate acetophenone.

(1a) 4-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:off-white solid, mp 137°-139° C.; Anal. calc'd for C₁₆ H₁₁ N₃ O₂ SBrF₃ :C., 43.07; H, 2.48; N, 9.42; Br, 17.91. Found: C, 43.01; H, 2.32; N,9.39; Br, 17.62.

(1b) 4-5-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:yellow solid, mp 154°-155° C.; Anal. calc'd for C₁₆ H₁₁ N₃ O₂ SClF₃ : C,47.83; H, 2.76; N, 10.46; Cl, 8.82. Found: C, 47.61; H, 2.85; N, 10.31;Cl, 8.43.

(1c) 4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:yellow solid, mp 157°-159° C.; Anal. calc'd for C₁₇ H₁₄ N₃ O₂ SF₃ : C,53.54; H, 3.70; N, 11.02. Found: C, 53.17; H, 3.81; N, 10.90.

(1d) 4-5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:white solid, mp 159°-160° C.; Anal. calc'd for C₁₆ H₁₁ N₃ O₂ SClF₃ : C,47.83; H, 2.76; N, 10.46. Found: C, 47.47; H, 2.65; N, 10.31.

(1e) 4-5-(4-trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:yellow solid, mp 144°-145° C.; Anal. calc'd for C₁₇ H₁₁ N₃ O₂ SF₆ : C,46.90; H, 2.55; N, 9.65. Found: C, 46.98; H, 2.57; N, 9.61.

(1f) 4-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:mp 168°-169° C.; Anal. calc'd for C₁₆ H₁₁ N₃ O₂ SF₄ : C, 49.87; H, 2.88;N, 10.90. Found: C, 49.83; H, 2.89; N, 10.86.

(1g) 4- 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:mp 164°-165° C.; Anal. calc'd for C₁₆ H₁₂ N₃ O₂ SF₃ : C, 52.31; H, 3.29;N, 11.43. Found: C, 52.14; H, 3.07; N, 11.34.

(1h) 4-5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:mp 153°-154° C.; Anal. calc'd for C₁₇ H₁₄ N₃ O₃ SF₃ : C, 51.38; H, 3.55;N, 10.57. Found: C, 51.00; H, 3.48; N, 10.24.

(1i) 4-5-(4-trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:white solid, mp 101°-103° C.; Anal. calc'd for C₁₇ H₁₁ N₃ O₃ SF₆ : C,45.24; H, 2.46; N, 9.31. Found: C, 45.22; H, 2.37; N, 9.29.

(1j) 4-5-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide:white solid, mp 126°-128° C.; Anal. calc'd for C₁₇ H₁₄ N₃ O₂ SF₃ : C,53.54; H, 3.70; N, 11.02. Found: C, 53.52; H, 3.55; N, 11.06.

EXAMPLE 2 ##STR15## 4-5-(4-Chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4-difluoro-1-4(chloro)-phenyl!-butane-1,3-dione.

Ethyl difluoroacetate (24.82 g, 200 mmol) was placed in a 500 mLthree-necked round bottom flask, and dissolved in diethyl ether (200mL). To the stirred solution was added 25 weight % sodium methoxide inmethanol (48 mL, 210 mmol) via an addition funnel over a 2 minuteperiod. Next, 4'1-chloroacetophenone (25.94 g, 200 mmol) was dissolvedin diethyl ether (50 mL), and added to the reaction dropwise over 5minutes. After stirring overnight (18 hours), 1N HCl (250 mL) and ether(250 mL) were added. The organic layer was collected, washed with brine(250 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give46.3 g of a yellow solid. The solid was recrystallized from methylenechloride and iso-octane to give 31.96 g, 69% of the dione, mp 65°-66.5°C.

Step 2: Preparation of 4-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

4-Sulphonamidophenyl hydrazine hydrochloride (1.45 g, 6.5 mmol 1.3equivalent) and 4,4-difluoro-1- 4-(chloro)phenyl!-butane-1,3-dione (1.16g, 5 mmol) were dissolved in ethanol (10 mL). The reaction was heated toreflux and stirred for 20 hours. After cooling to room temperature, thereaction mixture was concentrated in vacuo. The residue was taken up inethyl acetate (100 mL) and washed with water (100 mL) and brine (100mL), dried over MgSO₄, filtered, and concentrated in vacuo to give 1.97g of a light brown solid which was recrystallized from ethanol and waterto give 4-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide,1.6 g, 83% yield, mp 185°-186° C.

EXAMPLE 3 ##STR16##

4- 4-(Aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate

Step 1: Preparation of methyl-4- 4-(chloro)phenyl!-2,4-dioxobutanoate.

Dimethyl oxalate (23.6 g, 200 mmol) was placed in a 500 mL three-neckedround bottom flask, and dissolved in diethyl ether (200 mL). To thestirred solution was added 25 weight % sodium methoxide in methanol (48mL, 210 mmol) via an addition funnel over a 2 minute period. Next,4'-chloroacetophenone (25.94 g, 200 mmol) was dissolved in diethyl ether(50 mL), and added to the reaction dropwise over 3 minutes. Afterstirring overnight (18 hours), 1N HCl (400 mL) and ethyl acetate (750mL) were added. The organic layer was collected, washed with brine (350mL), dried over MgSO₄, filtered, and concentrated in vacuo to give 45.7g of a yellow solid. The solid was recrystallized from ethyl acetate andiso-octane to give 23 g, 48% of the dione, mp 108.5°-110.5° C.

Step 2: Preparation of 4-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate.

4-Sulphonamidophenyl hydrazine hydrochloride (1.45 g, 6.5 mmol 1.3equivalent) and methyl-4- 4-(chloro)phenyl!-2,4-dioxobutanoate (1.2 g, 5mmol) were dissolved in ethanol (50 mL). The reaction was heated toreflux and stirred for 20 hours. After cooling to room temperature, thereaction mixture was concentrated in vacuo. The residue was taken up inethyl acetate (200 mL) and washed with water (100 mL) and brine (100mL), dried over MgSO₄, filtered and concentrated in vacuo to give 1.7 gof a light brown solid which was recrystallized from methanol and waterto yield 1.6 g, 85% of a white solid. This material was dissolved inmethanol (150 mL) and 3N NaOH (75 mL) and stirred at reflux for 3 hours.The methanol was removed in vacuo and the aqueous solution acidifiedwith concentrated HCl. The product was then extracted into ethyl acetate(200 mL) which was washed-with brine (100 mL), dried over MgSO₄ filteredand concentrated to give 4-4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate,1.4 g, 74%, mp 135° C. (decomposed).

EXAMPLE 4 ##STR17## 4-4-(Aminosulfonyl)phenyl!-5-(4-chlorophenyl)1H-pyrazole-3-carboxamide

4- 4-(Aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate(1.08 g, 2.86 mmol), HOBt (0.66 g, 4.3 mmol) and EDC (0.66 g, 3.4 mmol)were dissolved in dimethylformamide (DMF) (20 mL) and stirred at ambienttemperature for 5 minutes. To this solution was added NH40H (30%, 2.9mL) and the reaction stirred for an additional 18 hours. This solutionwas then poured into ethyl acetate (200 mL) and 1N HCl (200 mL), shakenand separated. The organic layer was washed with saturated NaHCO₃ (150mL) and brine (150 mL), dried over MgSO₄, filtered and concentrated toyield 0.9 g of a white solid which was recrystallized from ethyl acetateand isooctane to yield 4- 4-(aminosulfonyl)phenyl!-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide, 0.85 g, 79%, mp108°-110° C.

EXAMPLE 5 ##STR18## 4- 5-(4-Methylthio!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4-difluoro-1-4(methylthio)phenyl!-butane-1,3-dione

Ethyl difluoroacetate (7.4 g, 60 mmol) was placed in a 500 mLthree-necked round bottom flask, and dissolved in diethyl ether (60 mL).To the stirred solution was added 25 weight % sodium methoxide inmethanol (14.4 mL, 63 mmol) via an addition funnel over a 2 minuteperiod. Next, 4'-methylthio acetophenone (9.97 g, 60 mmol) was dissolvedin diethyl ether (20 mL), and added to the reaction dropwise over 5minutes. After stirring overnight (16 hours), 1N HCl (150 mL) and ether(150 mL) were added. The organic layer was collected, washed with brine(150 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give13.4 g of a light-brown solid. The solid was recrystallized from ethanoland water to give 9.9 g, 68% of the dione, mp 68°-70° C.

Step 2: Preparation of 4- 5-(4-methylthio!phenyl)3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide.

4-Sulphonamidophenyl hydrazine hydrochloride (1.34 g, 6 mmol 1.2equivalent) and 4,4-difluoro-1- 4-(methylthio) phenyl!-butane-1,3-dione(1.22 g, 5 mmol) were dissolved in ethanol (50 mL). The reaction washeated to reflux and stirred for 20 hours. After cooling to roomtemperature, the reaction mixture was concentrated in vacuo. The residuewas taken up in ethyl acetate (200 mL) and washed with water (100 mL)and brine (100 mL), dried over MgSO₄, filtered and concentrated in vacuoto give 1.8 g of a light brown solid which was recrystallized fromethanol and water to yield 4- 5-(4-methylthio!phenyl)-3-(difluoromethyl)-1H-pyrazol-1yl!benzenesulfonamideas a white solid 1.14 g, 58%, mp 157°-158° C.

EXAMPLE 6 ##STR19## 4- 5-(4-Methylsulfonyl!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

4- 5-(4-Methylthio!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide(0.5 g, 1.27 mmol) was dissolved in methylene chloride (30 mL) andcooled to 0° C. To this solution was added m-chloroperoxybenzoic acid(MCPBA) (60%, 0.77 g, 2.7 mmol) and the solution was allowed to warm toroom temperature while stirring for 18 hours. A solution of Na₂ S₂ O₅ (2g) in H₂ O (25 mL) was added to the reaction mixture and the solutionstirred vigorously for 0.5 hour. The layers were separated and theorganic layer was washed with saturated NaHCO₃ (30 mL) and brine (30mL), dried over Na₂ SO₄ and concentrated to yield 4- 5-(4-methylsulfonyl! phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide as a white solid, 0.22 g, 40%, mp=209°-210° C.

EXAMPLE 7 ##STR20## 4- 5-(2,4-Difluoro!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4,4-trifluoro-1-2,4(difluoro)phenyl!-butane-1,3-dione Ethyl trifluoroacetate (2.19 g, 15mmol) was placed in a 100 mL round bottom flask, and dissolved in ether(10 mL). To the stirred solution was added 25 weight % sodium methoxide(3.35 g, 15 mmol) followed by 2',4'-difluoroacetophenone (2.11 g, 13mmol). The reaction was stirred at room temperature overnight (15.8hours), then poured into a separatory funnel and washed with 3N HCl (20mL), brine (20 mL), dried over MgSO₄, and concentrated in vacuo to givea yellow oil which solidified after cooling in dry ice. (2.67 g, 78%). ¹H NMR (CDCl₃) 300 MHz 15.00 (br s, 1H), 8.04 (m, 1H), 7.04 (m,1H), 6.94(m,1H), 6.68 (s,1H) ¹⁹ F NMR (CDCl₃) 300 MHz: -76.88 (s), -99.93(m),-103.92(m) M+Li 259.

Step 2: Preparation of 4- 5-(2.4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (2.31 g, 10.3 mmol) wasadded to a stirred solution of the diketone (2.37 g, 9.4 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred overnight(15.5 hours). After cooling to room temperature, the ethanol was removedin vacuo. The residue was dissolved in ethyl acetate, washed two timeswith water, washed two times with brine, dried over MgSO₄, andconcentrated in vacuo to give a brown foam which was recrystallized fromethyl acetate/isooctane to give the pyrazole as a tan solid (1.94 g, mp127°-30° C., 51% ). ¹ H NMR (CDCl₃) 300 MHz 7.91 (d, J=8.7 Hz, 2H), 7.45(d, J=8.5 Hz, 2H), 7.28 (m,1H), 6.96 (m,1H), 6.87 (m,1H), 6.81 (s, 1H)5.03 (br s, 1H); ¹⁹ F NMR (CDCl₃) 300 MHz: -62.87 (s), -105.60(m),-108.09(m) M+H 404.

EXAMPLE 8 ##STR21## 4- 5-(2,6-Difluoro!phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4,4-trifluoro-1-2,6(difluoro)phenyl!-butane-1,3-dione)

Ethyl trifluoroacetate (1.33 g, 9.3 mmol) was placed in a 100 mL roundbottom flask, and dissolved in ether (10 mL). To the stirred solutionwas added 25 weight % sodium methoxide (2.11 g, 9.8 mmol) followed by2',6'-difluoroacetophenone (1.32 g, 8.5 mmol). The reaction was stirredat room temperature overnight (15.8 hours), then poured into aseparatory funnel and washed with 3N HCl (20 mL), brine (20 mL), driedover MgSO₄, and concentrated in vacuo to give the diketone as a whitesolid (1.68 g, mp 40°-44° C., 79%). ¹ H NMR (CDCl₃) 300 MHz 14 .0 (br s,1H), 7.49 (m, 1H), 7.02 (m, 2H), 6.36 (s, 1H); ¹⁹ F NMR (CDCl₃) 300 MHz:-76.78 (s), -109.77(s) M+H 253.

Step 2: Preparation of 4- 5-(2,6-difluorolphenyl)3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (1.39 g, 6.2 mmol) wasadded to a stirred solution of the diketone (1.43 g, 5.7 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred overnight(15.75 hours). The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed two times with water, washed twotimes with brine, dried over MgSO₄, and concentrated in vacuo to give abrown solid (1.97 g) which was recrystallized from ethylacetate/isooctane to give the pyrazole as a white solid (1.00 g, mp178°-80° C., 44%). ¹ H NMR (acetone d⁶) 300 MHz 7.97 (d, J=8.9 Hz, 2H),7.62 (m,1H), 7.61 (d, J=8.9 Hz, 2H), 7.21 (s,1H), 7.16 (t, J=8.5 Hz,2H), 6.75 (br s, 2H); ¹⁹ F NMR (acetone d⁶) 300 MHz: -63.26 (s),-112.17(s) M+H 404.

EXAMPLE 9 ##STR22## 4-5-(4-Cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4,4-trifluoro-1-4(cyano)phenyl!-butane-1,3-dione.

Ethyl trifluoroacetate (5.91 g, 41.6 mmol) was placed in a 100 mL roundbottom flask, and dissolved in ether (30 mL). To the stirred solutionwas added 25 weight % sodium methoxide (9.02 g, 41.7 mmol) followed by4-acetylbenzonitrile (5.46 g, 37.6 mmol). The reaction was stirred atroom temperature for 4.2 hours, then treated with 1N HCl (50 mL). Thereaction mixture was filtered to collect the diketone as a white solid(3.63 g). The filtrate was extracted with ethyl acetate, washed withbrine (20 mL), dried over MgSO₄, and concentrated in vacuo, andrecrystallized from methylene chloride to give an additional 1.21 g(13%) of the diketone. (4.84 g, mp 124°-28° C., 53%). ¹ H NMR (CDCl₃)300 MHz 8.04 (d, J=8.5 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 6.59 (s, 1H); ¹⁹F NMR (CDCl₃) 300 MHz: -77.12 (s); M+H 242.

Step 2: Preparation of 4-5-(4-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (0.57 g, 2.5 mmol) wasadded to a stirred solution of the diketone (0.54 g, 2.2 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred for 5.5hours. The reaction mixture was filtered to remove the insoluble excesshydrazine and the ethanol was removed in vacuo. The residue wasdissolved in ethyl acetate, washed two times with water, washed oncewith brine, dried over MgSO₄, and concentrated in vacuo to give a yellowsolid which was recrystallized from ethyl acetate/isooctane to give thepyrazole as a yellow solid (0.52 g, mp 196°-97.50° C., 59% ). ¹ H NMR(CDCl₃) 300 MHz 7.95 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.47 (d,J=8.8 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 4.90 (br s, 2H); ¹⁹F NMR (CDCl₃) 300 MHz: -62.97 (s); M+H 393.

EXAMPLE 10 ##STR23## 4-5-(4-Chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl!benzenesulfonamide

Ethyl heptafluorobutyrate (5.23 g, 21.6 mmol) was placed in a 100 mLround bottom flask, and dissolved in ether (20 mL). To the stirredsolution was added 25 weight % sodium methoxide (4.85 g 22.4 mmol)followed by 4-chloroacetophenone (3.04 g, 19.7 mmol). The reaction wasstirred at room temperature overnight (15.9 hours) and treated with 3NHCl (17 mL). The organic layer was collected, washed with brine, driedover MgSO₄, concentrated in vacuo, and recrystallized from isooctane togive the diketone as a white solid (4.27 g, mp 27°-30° C., 62%). ¹ H NMR(CDCl₃) 300 MHz 15.20 (br s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7Hz, 2H), 6.58 (S, 1H); ¹⁹ F NMR (CDCl₃) 300 MHz: -80.94 (t), -121.01(t), -127.17 (s); M+H 351.

Step 2: Preparation of 4-5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (290 mg, 1.30 mmol) wasadded to a stirred solution of the diketone (400 mg, 1.14 mmol) inethanol (5 mL). The reaction was heated to reflux and stirred overnight(23.8 hours). The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed with water and brine, dried overMgSO₄, and concentrated in vacuo to give a white solid which was passedthrough a column of silica gel with ethyl acetate/hexane (40%) andrecrystallized from ethyl acetate/isooctane to give the pyrazole as awhite solid (0.24 g, mp 168°-71° C., 42%). ¹ H NMR (CDCl₃) 300 MHz 7.90(d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.19(d, J=8.5 Hz, 2H), 6.79 (s, 1 H), 5.20 (br s, 2H); ¹⁹ F NMR (CDCl₃) 300MHz: -80.48 (t), -111.54 (t), -127.07 (s).

EXAMPLE 11 ##STR24## 4-5-(4-Chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4-chloro-4,4-difluoro-1-4-(chloro)phenyl!-butane-1,3-dione.

Methyl 2-chloro-2,2-difluoroacetate (4.20 g, 29 mmol) was placed in a100 mL round bottom flask, and dissolved in ether (10 mL). To thestirred solution was added 25 weight % sodium methoxide (6.37 g, 29mmol) followed by 4'-chloroacetophenone (4.10 g, 26.5 mmol) The reactionwas stirred at room temperature overnight (20.4 hours), then poured intoa separatory funnel and washed with 3N HCl (15 mL), brine (20 mL), driedover MgSO₄, and concentrated in vacuo and recrystallized from isooctaneto give the diketone as a yellow solid (3.78 g, mp 53°-55° C., 53%). ¹ HNMR (CDCl₃) 300 MHz 14.80 (br s, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.50 (d,J=8.7 Hz, 2H), 6.49 (S, 1H); ¹⁹ F NMR (CDCl₃) 300 MHz: -66.03 (s); M+267.

Step 2: Preparation of 4-5-(4-chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (1.39 g, 6.2 mmol) wasadded to a stirred solution of the diketone (1.43 g, 5.7 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred overnight(15.75 hours). The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed with water and brine, dried overMgSO₄, and concentrated in vacuo to give a white solid which wasrecrystallized from ethyl acetate/isooctane to give the pyrazole as awhite solid (0.32 g, mp 130°-33° C., 41%). ¹ H NMR (CDCl₃) 300 MHz 7.90(d, J=8.9 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.19(d, J=8.7 Hz, 2H), 6.76 (s, 1 H), 5.13 (br s, 2H); ¹⁹ F NMR (CDCl₃) 300MHz: -48.44 (s); M+ 417/419.

EXAMPLE 12 ##STR25## 4-5-(4-Chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4,5,5,5-pentafluoro-1-4-(chloro)phenyl!-pentane-1,3-dione.

Ethyl pentafluoropropionate (6.31 g, 32.8 mmol) was placed in a 100 mLround bottom flask, and dissolved in ether (15 mL). To the stirredsolution was added 25 weight % sodium methoxide (7.90 g, 36.6 mmol)followed by 4'-chloroacetophenone (4.60 g, 29.8 mmol). The reaction wasstirred at room temperature overnight (20.1 hours), then poured into aseparatory funnel and washed with 3N HCl (20 mL)), brine (20 mL), driedover MgSO₄, and concentrated in vacuo to give the diketone as a yellowpowder which was recrystallized from isooctane to give yellow platelets.(7.07 g, mp 74°-77° C., 79%). ¹ H NMR (CDCl₃) 300 MHz 15.20 (br s, 1H),7.88 (d, J=8.9 Hz, 2H), 7.51 (d, J=8.9 Hz, 2H), 6.60 (S, 1H); ¹⁹ F NMR(CDCl₃) 300 MHz: -82.97 (t,J=2.2 Hz), -124.23 (s); M+H 301.

Step 2: Preparation of 4-5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (1.39 g, 6.2 mmol) wasadded to a stirred solution of the diketone (1. 43 g, 5.7 mmol) inethanol (10 ML). The reaction was heated to reflux and stirred overnight(15.75 hours). The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed water and brine, dried over MgSO₄,and concentrated in vacuo to give a white solid which was passed througha column of silica gel with ethyl acetate/hexane (16%) andrecrystallized from ethyl acetate/isooctane to give the pyrazole as awhite solid (0.32 g, mp 145.5°-50° C., 40% ). ¹ H NMR (CDCl₃) 300 MHz7.90 (d, J=8.9 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H),7.19 (d, J=8.5 Hz, 2H), 6.79 (s, 1 H), 5.18 (br s, 2H); ¹⁹ F NMR (CDCl₃)300 MHz: -84.66 (t), -113.70 (d).

EXAMPLE 13 ##STR26## 4-5-(4-Biphenyl)-3-(difluoromethyl)-1H-pyrazol-1yl!benzenesulfonamide

Step 1: Preparation of 4,4-difluoro-1- 4-biphenyl!butane-1,3-dione)

Ethyl trifluoroacetate (2.08 g, 16.8 mmol) was placed in a 100 mL roundbottom flask, and dissolved in ether (5 mL). To the stirred solution wasadded 25 weight % sodium methoxide (3.73 g,17.2 mmol) followed by4-acetylbiphenyl (2.97 g, 15.1 mmol) and THF (10 mL). The reaction wasstirred at room temperature overnight (16.4 hours), treated with 3N HCl(8 mL), and extracted with ethyl acetate. The organic layer wascollected and washed with brine, dried over MgSO₄, concentrated invacuo, and. recrystallized from methylene chloride/isooctane to give thediketone as a brown solid (3.24 g, mp 115°-18° C., 78%). ¹ H NMR (CDCl₃)300 MHz 15.40 (br s, 1H), 8.01 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.3 Hz,2H), 7.63 (d, J=7.o Hz, 2H), 7.49 (m, 3H), 6.61 (s, 1H), 6.02 (t, J=54.4Hz,1H); ¹⁹ F NMR (CDCl₃) 300 MHz: -126.91; M+ 274.

Step 2: Preparation of 4-5-(4-biphenyl)-3(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (0.40 g, 1.79 mmol) wasadded to a stirred solution of the diketone (0.44 g, 1.60 mmol) inethanol (5 mL). The reaction was heated to reflux and stirred overnight(23.6 hours). The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed with water (20 mL), washed with brine(20 mL), dried over MgSO₄, and concentrated in vacuo to give a brownsolid which was recrystallized from ethyl acetate/isooctane to give thepyrazole as a brown solid (0.48 g, mp 167°-70° C., 70%) ¹ H NMR (CDCl₃)300 MHz 7.91 (d, J=8.7 Hz, 2H), 7.59 (d, J=8.3 Hz, 4H), 7.26-7.51 (m,7H), 6.79 (s and t, J=54.9 Hz 2 H), 4.89 (br s, 2H); ¹⁹ F NMR (CDCl₃)300 MHz: -112.72 (d); M+ 425.

EXAMPLE 14 ##STR27## 4-5-(2-Pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4-difluoro-1-(2pyrazinyl)-butane-1,3-dione.

Ethyl difluoroacetate (2.23 g, 18 mmol) was placed in a 100 mL roundbottom flask and dissolved in ether (10 mL). To the stirred solution wasadded 25 weight % sodium methoxide (4.68 g, 22 mmol) followed byacetylpyrazine (2.00 g,16 mmol). After two hours stirring at roomtemperature, a precipitate formed and THF (10 mL) was added to thereaction. The reaction was stirred an additional 25.9 hours, thentreated with 3N HCl (10 mL). The organic layer was collected, washedwith brine (20 mL), dried over MgSO₄, and concentrated in vacuo andrecrystallized from methylene chloride/isooctane to give the diketone asa brown solid (2.23 g, mp 103°-110° C., 68%). ¹ H NMR (CDCl₃) 300 MHz14.00 (br s, 1H), 9.31 (d, J=1.4 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.68(dd, J=1.4 Hz 2.4 Hz, 1H), 7.20 (s, 1H), 6.03 (t, J=54.0 Hz, 1H); ¹⁹ FNMR (CDCl₃) 300 MHz: -127.16 (d); M+ 200.

Step 2: Preparation of 4-5-(2-pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (0.37 g, 1.65 mmol) wasadded to a stirred suspension of the diketone (0.30 g, 1.50 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred for 5.3hours. The ethanol was removed in vacuo, and the residue was dissolvedin ethyl acetate, washed with water (20 mL), brine (20 mL), dried overMgSO₄, and concentrated in vacuo to give a brown solid (0.36 g) whichwas recrystallized from ethyl acetate/ethanol/isooctane to give thepyrazole as a brown solid (0.20 g, mp 191°-94° C., 38%). ¹ H NMR(acetone d⁶) 300 MHz 8.94(d, J=1.4 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.52(dd, J=1.4 Hz 2.4 Hz, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.7 Hz,2H), 7.30 (s, 1H), 7.02 (t, J=54.6 Hz, 1H), 6.73 (br s, 2 H); ¹⁹ F NMR(acetone d⁶) 300 MHz: -113.67 (d); M+ 351.

EXAMPLE 15 ##STR28## 4-5-(5-Chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4-difluoro-1-5-chloro-2-thienyl!-butane-1,3-dione.

Ethyl difluoroacetate (3.51 g, 28.3 mmol) was placed in a 100 mL roundbottom flask and dissolved in ether (10 mL). To the stirred solution wasadded 25 weight % sodium methoxide (6.12 g, 28.3 mmol) followed by2-acetyl-5-chlorothiophene (4.12 g, 25.6 mmol). A pink precipitateformed after 5 minutes which was dissolved by adding ether (10 mL) andTHF (10 mL) to the reaction. The reaction was stirred at roomtemperature overnight (15.75 hours), then treated with 3N HCl (15 mL).The organic layer was collected and washed with brine (20 mL), driedover MgSO₄, and concentrated in vacuo to give a red solid (5.94 g) whichwas recrystallized from methylene chloride/isooctane to give thediketone as a yellow solid (2.02 g, mp 72°-77° C., 33%). ¹ H NMR (CDCl₃)300 MHz 14.60 (br s, 1H), 7.57 (d, J=4.2 Hz, 1H), 7.01 (d, J=4.2 Hz,1H), 6.32 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); ¹⁹ F NMR (CDCl₃) 300 MHz:-127.01 (d); M+ 238.

Step 2: Preparation of 4-5-(5-chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzene

The 4-sulfonamidophenyl hydrazine hydrochloride (0.31 g, 1.39 mmol) wasadded to a stirred solution of the diketone (0.30 g, 1.26 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred 5.5hours. The ethanol was removed in vacuo, and the residue was dissolvedin ethyl acetate, washed with water (20 mL), washed with brine (20 mL),dried over MgSO₄, and concentrated in vacuo to give a yellow solid (0.55g) which was recrystallized from ethyl acetate/isooctane to give thepyrazole as a white solid (0.38 g, mp 168°-70° C., 78%). ¹ H NMR(acetone d⁶) 300 MHz 8.03 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H),7.04 (m, 4H), 6.76 (br s, 2 H); ¹⁹ F NMR (acetone d⁶) 300 MHz: -113.71(d); ¹³ C NMR (acetone d⁶) 300 MHz 148.01(t), 144.69, 141.64, 137.70,131.59, 128.90, 128.53, 127.48, 127.40 ,126.47, 111.36(t), 105.89(t); M+389/391.

EXAMPLE 16 ##STR29## 4-5-(4-(Morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4-difluoro-1-4(morpholino)-phenyl!-butane-1,3-dione

Ethyl difluoroacetate (2.30 g, 18.5 mmol) was placed in a 100 mL roundbottom flask and dissolved in THF (25 mL). To the stirred solution wasadded 25 weight % sodium -methoxide (4.90 g, 22.6 mmol) followed by4'-morpholinoacetophenone (3.45 g, 16.8 mmol). The reaction was stirredat room temperature overnight (15.8 hours), then treated with 3N HCl (13mL). The reaction was extracted with ethyl acetate (20 mL), washed withbrine (20 mL), dried over MgSO₄, and concentrated in vacuo to give agreen solid (4.36 g) which was recrystallized from methylenechloride/isooctane to give the diketone as a yellow solid (3.27 g, mp102°-3° C., 69%). ¹ H NMR (CDCl₃) 300 MHz 15.80 (br s, 1H), 7.86 (d,J=9.1 Hz, 2H), 6.90 (d, J=9.l1 Hz, 2H), 6. 46 (s, 1H), 5.99 (t, J=54.4Hz, 1H), 3.84 (m,4 H), 3.36 (m,4H) ; ¹⁹ F NMR (CDCl₃) 300 MHz: -126.75(d); M+ 283.

Step 2: Preparation of 4-5-(4-(morpholino)phenyl)-3-(difluoromethyl)-1H-,pyrazol-1-yl!benzenesulfonamide.

The 4-sulfonamidophenyl hydrazine hydrochloride (0.20 g, 0.89 mmol) wasadded to a boiling solution of the diketone (0.23 g, 0.81 mmol) inethanol (5 mL). The reaction was stirred 5.0 hours. The ethanol wasremoved in vacuo, and the residue was dissolved in ethyl acetate, washedwith water (20 mL), washed with brine (20 mL), dried over MgSO₄, andconcentrated in vacuo to give a yellow foam (0.36 g) which wasrecrystallized from methylene chloride/isooctane to give the pyrazole asa yellow solid (0.25 g, mp 167°-71° C., 71%). ¹ H NMR (CDCl₃) 300 MHz7.88 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.9 Hz, 2H), 7.10 (d, J=8.9 Hz, 2H),6.86 (d, J=9.1 Hz, 2H), 6.75 (t, J=55.0 Hz, 1H), 6,67 (s, 1H) 4.91 (brs, 2H), 3.86 (m, 4H), 3.21 (m, 4H); ¹⁹ F NMR (CDCl₃) 300 MHz: -112.67(d); M+ 434.

EXAMPLE 17 ##STR30## 4-5-(1-Cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4-difluoro-1- 2cyclohexenyl!-butane-1,3-dione.

Ethyl difluoroacetate (4.71 g, 38 mmol) was placed in a 100 mL roundbottom flask and dissolved in ether (20 mL). To the stirred solution wasadded 25 weight % sodium methoxide (9.68 g, 45 mmol) followed by1-acetyl1-cyclohexene (4.27 g, 34 mmol). The reaction was stirred atroom temperature overnight (17.5 hours), then treated with 3N HCl (20mL). The organic layer was collected and washed with brine (20 mL),dried over MgSO₄, and concentrated in vacuo to give a brown oil (6.48 g,93%). ¹ H NMR (CDCl₃) 300 MHz 15.00 (br s, 1H), 6.09 (s,1H), 5.92 (t,J=54.4 Hz,1H), 2.31 (m, 4H), 1.64 (m, 4H); ¹⁹ F NMR (CDCl₃) 300 MHz:-126.94; M+ 202.

Step 2: Preparation of 4-5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (0.71 g, 3.17 mmol) wasadded to a stirred solution of the diketone (0.58 g, 2.87 mmol) inethanol (5 mL). The reaction was heated to reflux and stirred overnight(14.6 hours). The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed with water (35 mL), washed with brine(35 mL), dried over MgSO₄, and concentrated in vacuo to give a brown oilwhich was passed through a column of silica gel with 16% ethylacetate/hexane to isolate the pyrazole as a white solid (0.41 g, mp160°-61° C., 40%) ¹ H NMR (CDCl₃) 300 MHz 7.96 (d, J=8.5 Hz, 2H), 7.67(d, J=8.6 Hz, 2H), 6.70 (t, J=55.0 Hz 1H), 6.50 (s, 1H), 5.90 (br s,1H), 5.22 (br s, 2H), 2.02-2.11(m, 4H), 1.70-1.61 (m, 4H); ¹⁹ F NMR(CDCl₃) 300 MHz: -112.69 (d); M+ 353.

EXAMPLE 18 ##STR31## 4-5-(1-Cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4- 5-(1-cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide (0.31 g, 0.88 mmol) was dissolved inethanol (15 mL), 10% palladium on charcoal was added, and the suspensionwas stirred at room temperature under hydrogen (36 psi) for 18.25 hours.The reaction was filtered through celite, and the ethanol removed invacuo to give a white solid, which was recrystallized from methylenechloride/isooctane (0.31 g, mp 199-203° C., 99%). ¹ H NMR (acetone d⁶)300 MHz 8.05 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 6.69 (t, J=55.0Hz 1H), 6.47 (s, 1H), 5.02 (br s, 2H), 2.67 (m, 1H), 1.71°-1.88(m, 5H),1.24-1.43 (m, 5H); ¹⁹ F NMR (acetone d⁶) 300 MHz: -112.86 (d).

EXAMPLE 19 ##STR32## 4-5-(5-Bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1. Preparation of 4,4-difluoro-1-5-bromo-2thienyl!-butane-1,3-dione.

Ethyl difluoroacetate (2.43 g, 19.6 mmol) was placed in a 100 mL roundbottom flask, and dissolved in ether (15 ML). To the stirred solutionwas added 25 weight % sodium methoxide (4.23 g, 19.5 mmol) followed by2acetyl-5-bromothiophene (3.59 g, 17.5 mmol). After two hours aprecipitate formed and THF (15 mL) was added to allow stirring tocontinue. The reaction was stirred at room temperature 6.2 hours, thentreated with 3N HCl (20 mL). The organic layer was collected and washedwith brine, dried over MgSO₄, and concentrated in vacuo to give a yellowoil which was crystallized from methylene chloride/isooctane to giveyellow needles (3.63 g, mp 83.5°-85° C., 73%). ¹ H NMR (CDCl₃) 300 MHz14.60 (br s, 1H), 7.53 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 7.19(m, 1H), 6.32 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); ¹⁹ F NMR (CDCl₃) 300MHz: -127.00 (d); M+ 282.

Step 2. Preparation of 4-5-(5-bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (0.42 g, 1.88 mmol) wasadded to a stirred solution of the diketone (0.48 g, 1.70 mmol) inethanol (5 mL). The reaction was heated to reflux and stirred overnight(17.25 hours). The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed with water (20 mL), washed with brine(20 mL), dried over MgSO₄, and concentrated in vacuo to give a whitesolid (0.67 g) which was recrystallized from ethyl acetate/isooctane togive the pyrazole as a white solid (0.39 g, mp 168°-69° C., 53%). ¹ HNMR (acetone d⁶) 300 MHz 8.03 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.7Hz, 2H),7.16 (d and part of CF₂ H triplet, J=4.0 Hz 1.25 H), 6.97 (m and part ofCF₂ H triplet, 2.5H) 6.78 (br s and part of CF₂ H triplet, 2.25 H); ¹⁹ FNMR (acetone d⁶) 300 MHz: -113.70 (d); M+Li 440/442.

EXAMPLE 20 ##STR33## 4-5-(2-Thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4-difluoro-1- 2-thienyl!butane-1,3-dione.

Ethyl difluoroacetate (1.84 g,14.8 mmol) was placed in a 100 mL roundbottom flask and dissolved in ether (5 mL). To the stirred solution wasadded 25 weight % sodium methoxide (3.39 g, 15.7 mmol) followed by2acetylthiophene (1.72 g,13.6 mmol). The reaction was stirred at roomtemperature overnight (15.67 hours), then treated with 3N HCl (8 ML).The organic layer was collected and washed with brine, dried over MgSO₄,concentrated in vacuo, and recrystallized from methylenechloride/isooctane to give a brown solid (1.38 g, mp 78°-80° C., 50%). ¹H NMR (CDCl₃) 300 MHz 14.90 (br s, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.71 (d,J=3.8 Hz, 1H), 7.19 (m, 1H), 6.41 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); ¹⁹ FNMR (CDCl₃) 300 MHz: -126.98 (d); M+ 204.

Step 2: Preparation of 4-5-(2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The 4-sulfonamidophenyl hydrazine hydrochloride (0.43 g, 1.92 mmol) wasadded to a stirred solution of the diketone (0.36 g, 1.76 mmol) inethanol (5 mL). The reaction was heated to reflux and stirred overnight(17.67 hours). The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed with water (20 mL), washed with brine(20 mL), dried over MgSO₄, and concentrated in vacuo to give a brownsolid which was recrystallized from ethyl acetate/isooctane to give thepyrazole as brown needles (0.30 g, mp 190°-91° C., 48%). ¹ H NMR(acetone d⁶) 300 MHz 8.00 (d, J=8.2 Hz, 2H), 7.62 (m, 3H), 7.11 (m, andpart of CF2H triplet, 2.25H), 6.93 (s and part of CF2H triplet, 1.5H)6.76 (br s and part of CF₂ H triplet, 2.25 H); ¹⁹ F NMR (acetone d⁶) 300MHz: -113.60 (d); 13C NMR (acetone d⁶) 300 MHz 146.96(t), 144.43,141.98, 138.84, 129.53, 129.02, 128.38, 127.86, 127.26 ,126.36,114.46(t), 105.57(t); M+Li 367.

EXAMPLE 21 ##STR34## 4- 5-(4-Trifluoromethyl!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 4,4-difluoro-1-4(trifluoromethyl)phenyl!-butane-1,3-dione, Ethyl difluoroacetate (2.78g, 22.4 mmol) was placed in a 100 mL round bottom flask and dissolved inether (10 mL). To the stirred solution was added 25 weight % sodiummethoxide (6.02 g, 27.8 mmol) followed by4'-(trifluoromethyl)acetophenone (3.80 g, 20.2 mmol) and THF (20 ML).The reaction was stirred at room temperature overnight (15.6 hours),then treated with 3N HCl (20 mL). The organic layer was collected andwashed with brine, dried over MgSO₄, concentrated in vacuo to give abrown oil (4.88 g, 91%). ¹ H NMR (acetone d⁶) 300 MHz 15.10 (br s, 1H),8.03 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 6.59 (s,1H), 6.02 (t,J=54.2 Hz, 1H); ¹⁹ F NMR (acetone d⁶) 300 MHz: -63.70 (s), -127.10 (d);M+ 266.

Step 2: Preparation of 4- 5-(4-trifluoromethyl!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

The diketone (0.41g, 1.54 mmol) was added to a stirred suspension of4-sulfonamidophenyl hydrazine hydrochloride (0.39 g, 1.74 mmol) inethanol (5 mL). The reaction was heated to reflux and stirred overnight(17.4 hours). The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed with water (20 mL), washed with brine(20 mL), dried over MgSO₄, and concentrated in vacuo to give a brownsolid which was recrystallized from ethyl acetate/isooctane to give thepyrazole as a tan solid (0.30 g, mp 202°-5° C., 46%). ¹ H NMR (acetoned⁶) 300 MHz 7.95 (d, J=8.9 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H), 7.62 (d,J=8.1 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 7.03 (s,1H), 6.99 (t, J=54.6 Hz,1H), 6.73 (br s, 2H); ¹⁹ F NMR (acetone d⁶) 300 MHz: -63.69 (s), -113.57(d); M+H 418.

EXAMPLE 22 ##STR35## 4-5-(3,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

3,4-Dichloroacetophenone (6.24 g, 33 mmol) was dissolved in 25 mLmethanol and 25% NaOMe in methanol (9 mL, 39.4 mmol) was added. Themixture was stirred at 25° C. for 5 minutes and ethyl trifluoroacetate(5 mL, 42 mmol) was added. The mixture was heated at 60° C. for 24hours, cooled and the volume reduced by 50%. The mixture was poured into100 mL of 10% HCl and extracted with four 75 mL portions of ethylacetate. The combined extracts were dried over Na₂ SO₄, filtered andconcentrated in vacuo to afford the crude diketone as a brown gum (8.54g, 30 mmol) which was-used without further purification. The crudediketone (3.16 g, 11.1 mmol) and 4-sulfonamidophenylhydrazine.HCl (3.31g, 14.8 mmol) were dissolved in 75 mL of absolute ethanol and themixture stirred at reflux for 24 hours. The mixture was cooled, filteredand concentrated in vacuo to afford the crude pyrazole.Recrystallization from diethyl ether/hexane afforded the pure pyrazole(2.43 g, 51%) as a yellow solid, mp 145°-147° C.; Anal. calc'd for C₁₆H₁₀ N₃ O₂ SCl₂ F₃ : C, 44.05; H, 2.31; N, 9.63; Cl, 16.25. Found: C,44.00; H, 2.20; N, 9.63; Cl, 16.46.

EXAMPLE 23 ##STR36## 4-5-(2,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Following the procedure of Example 22, but substituting2,4-dichloroacetophenone for 3,4-dichloroacetophenone afforded 4-5-(2,4-dichlorophenyl)3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamideas a tan solid, mp 153°-155° C.; Anal. calc'd for C₁₆ H₁₀ N₃ O₂ SCl₂ F₃-0.10 H₂ O: C, 43.87; H, 2.35; N, 9.59. Found: C, 43.78; H, 2.13; N,9.56.

EXAMPLE 24 ##STR37## 4-5-Phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1-yl!benzenesulfonamide

A 60% dispersion of sodium hydride in mineral oil (4.0 g, 100 mmol) wastwice washed with hexane (100 mL each) and dried under a stream ofnitrogen. Ether (300 mL) was added followed by dropwise addition ofethanol (0.25 mL) and y-butyrolactone (4.0 mL, 52 mmol). The mixture wascooled to 10° C. and acetophenone (5.8 mL, 50 mmol) in ether (40 mL) wasadded dropwise over 1 hour. The mixture was warmed to 25° C. and stirredovernight. The mixture was cooled to 0° C. and quenched with ethanol (5mL) followed by 10% aqueous ammonium sulfate (100 mL). The organicsolution was separated, dried over Na₂ SO₄ and concentrated. The residuewas chromatographed on silica gel with 1:1 hexane/ethyl acetate to givethe desired diketone (3.4 g) as an oil. Pyridine (0.34 mL, 4.2 mmol) andthe diketone (700 mg, 3.4 mmol) in methanol (3 mL) were added to aslurry of 4-sulfonamidophenylhydrazine-HCl (750 mg, 3.4 mmol) inmethanol (8 mL). The mixture was stirred at 25° C. overnight andconcentrated in vacuo. The residue was dissolved in methylene chlorideand the solution washed with 1N HCl. The organic solution was separated,dried and concentrated. The residue was chromatographed on silica gelusing ethyl acetate to give the desired pyrazole (435 mg) as a solid:Anal. calc'd for C₁₈ H₁₉ N₃ O₃ S: C, 60.49; H, 5.36; N, 11.75. Found: C,60.22; H, 5.63; N, 11.54.

EXAMPLE 25 ##STR38##

4-5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl!benzenesulfonamide

Following the procedure of Example 24, but substituting4-fluoroacetophenone for acetophenone afforded 4-5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl!benzenesulfonamide.Anal. calc'd for C₁₈ H₁₈ N₃ O₃ SF-0.25 H₂ O: C, 56.90; H, 4.91; N,11.05. Found: C, 56.80; H, 4.67; N, 11.02.

EXAMPLE 26 ##STR39## 4-4-(Aminosulfonyl)phenyl!-5-(4-fluorophenyl)-1H-pyrazole!-3-propanoicacid

Jones reagent (0.64 mL of a 2.67M solution) was added dropwise to asolution of 4-5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl!benzenesulfonamidefrom Example 25 (295 mg, 0.78 mmol) in acetone (8 mL). The mixture wasstirred at 25° C. for 2 hours. The solution was filtered and thefiltrate concentrated in vacuo. The residue was dissolved in ethylacetate and washed with water (3X). The organic solution was dried overMgSO₄ and concentrated. The residual oil was crystallized fromether/hexane to give the desired acid. (149 mg, mp 180°-182 C.) Anal.calc'd for C₁₈ H₁₆ N₃ O₄ SF: C, 55.52; H, 4.14; N, 10.79. Found: C,55.47; H, 4.22; N, 10.50.

EXAMPLE 27 ##STR40## 4,5-Dihydro-4- 3-trifluoromethyl!-1H-benzg!indazol-1-yl!benzenesulfonamide

Step 1: Preparation of 2-trifluoroacetyl-1tetralone.

A 250 mL one necked round bottomed flask equipped with a refluxcondenser, nitrogen inlet and provisions for magnetic stirring wascharged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL ofether. To this solution was added 48 mL of 25% sodium methoxide inmethanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in 50mL of ether was then added over about 5 min. The reaction mixture wasthen stirred at room temperature for 14 h and then was diluted wih 100mL of 3N HCl. The phases were separated and the organic layer washedwith 3N HCl, brine, dried over anhyd. MgSO₄, filtered and concentratedin vacuo. The residue was then taken up in 70 mL of boilingethanol/water and allowed to cool to room temperature whereupon crystalsof 2-trifluoroacetyl-1-tetralone formed which were isolated byfiltration and air dried to give 32 g, 81% of pure product with Tap48°-49° C. ¹ H NMR CDCl₃ δ2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz,1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19 F NMR CDCl₃ δ-72.0. EIGC-MS M+=242.

Step 2: Preparation of 4,5-dihydro-4- 3-(trifluoromethyl)-1H-benzg!indazol-1-yl!benzenesulfonamide.

A 100 mL one necked round bottomed flask equipped with reflux condenser,nitrogen inlet and provisions for magnetic stirring was charged with2trifluoroacetyl-1-tetralone (1.21 g, 5.0 mmol), 4sulfonamidophenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mL of absoluteethanol. The solution was then warmed to reflux for 15 h and thenconcentrated in vacuo. The residue was dissolved in ethyl acetate andthen washed with water, brine, dried over anhyd. MgSO₄, filtered andconcentrated in vacuo. The residue was recrystallized from a mixture ofethyl acetate and isooctane to give g, 71% of pure product with mp257°-258° C. ¹ H NMR (CDCl₃ /CD₃ OD, 4:1) 67 2.7 (m, 2H), 2.9 (m, 2H),6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92(m, 2H); 19 F NMR CDCl₃ δ-62.5. FAB-MS M+H =394.

EXAMPLE 28 ##STR41## 4-5-(4-Chlorophenyl)-4-chloro-1H-pyrazol-1-yl!benzenesulfonamide

Step 1. Preparation of 3-(4-chlorophenyl)-3-ketopropionaldehyde.

A 4-necked round-bottomed flask equipped with mechanical stirrer,nitrogen inlet, reflux condenser, constant pressure addition funnel andthermometer was charged with 4-chloroacetophenone (77.0 g, 0.5 mol),ethyl formate (40.8 g, 0.55 mol) and 800 mL of ether. The strirrer wasstarted and the solution treated with a solution of 25% sodium methoxidein methanol (123 g, 0.55 mol) from the addition funnel over about 0.5hour. A heavy white precipitate formed as the sodium methoxide wasadded. The reaction was stirred at room temperature for 5 hours and wasthen diluted with an additional 800 mL of ether, the precipitate wasisolated on a Buchner funnel and washed with thouroughly with ether. Theprecipitate was dried in vacuo and then placed in a large Erlenmeyerflask and acidified with 3N HCl and then extracted with ethyl acetate.The ethyl acetate solution was washed with brine, dried over anhydrousMgSO4, filtered and concentrated in vacuo to give a thick orange oil,60.9 g, 67% of 3-(4-chlorophenyl)-3-ketopropionaldehyde, IR (neat)-1585cm⁻¹.

Step 2. Preparation of 4-5-(4-chlorophenyl)-1H-pyrazol-1-yl!benzenesulfonamide.

A 250 mL one-necked round-bottomed flask equipped with reflux condenser,nitrogen inlet and provisions for magnetic stirring was charged with3-(4-chlorophenyl)-3-ketopropionaldehyde (18.3 g, 0.1 mol),4-sulfonamidophenylhydrazine hydrochloride (11.2 g, 0.05 mol) and 100 mLof absolute ethanol. The solution was heated to reflux for 15 hour andthen diluted with 100 mL of water and allowed to stand whereupon a whitesolid formed that was isolated by filtration on a Buchner funnel and airdried to provide 12.6 g, 76% of 4-5-(4-chlorophenyl)-1H-pyrazol-1-yl!benzenesulfonamide, mp 185°-187° C. ¹H nmr (CDCl₃ /300 MHz) 7.89(d, J=8.7Hz, 2H), 7.76(d, J=1.8Hz, 1H),7.43(d, J=8.7Hz, 2H), 7.34(d, J=8.7Hz, 2H), 7.17(d, J=8.7Hz, 2H),6.53(d, J=1.8Hz, 1H), 4.93(brs, 2H), mass spectrum MH⁺ =334.

Step 3. Preparation of 4-5-(4-chlorophenyl)-4chloro-1H-pyrazol-1-yl!benzenesulfonamide.

A 100 mL three-necked round-bottomed flask equipped with refluxcondenser, gas dispersion tube and provisions for magnetic stirring wascharged with 4- 5(4-chlorophenyl)-1H-pyrazol-1-yl!benzenesulfonamide(500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. The solution wasstirred at room temperature and treated with a stream of chlorine gasfor a period of 15 minutes. The solution was then stirred at roomtemperature for 1.25 hours and then diluted with 100 mL of water. Thesolution was then extracted three times with ether and the combinedethereal phase washed with brine, dried over anhyd. MgSO₄, filtered, andconcentrated in vacuo to give a white solid that was recrystallized fromether/petroleum ether to provide 400 mg, 75% of 4-5-(4-chlorophenyl)-4-chloro-1H-pyrazol-1-yl!benzenesulfonamide, ¹ H nmr(CDCl₃ /300 MHz) 8.06 (s, 1H), 7.81(d, J=8.4 Hz, 2H), 7.53(d, J=8.4 Hz,2H), 7.43(brs, 2H), 7.42(d, J=8.4 Hz, 2H), 7.32(d, J=8.4 Hz, 2H).

EXAMPLE 29 ##STR42## 4-5-(4-Chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazol-1-yl!benzenesulfonamide

A 100 mL three-necked round-bottomed flask equipped with refluxcondenser, gas dispersion tube and provisions for magnetic stirring wascharged with 4-5-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl!benzenesulfonamide(500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. The solution wasstirred at room temperature and treated with a stream of chlorine gasfor a period of 15 minutes. The solution was then stirred at roomtemperature for 1.25 hours and then diluted with 100 mL of water. Thesolution was then extracted three times with ether and the combinedethereal phase washed with brine, dried over anhyd. MgSO₄, filtered, andconcentrated in vacuo to give a white solid that was recrystallized fromether/petroleum ether to provide 390 mg, 75% of 4-5-(4-chlorophenyl)-4-chloro-3-trifluoromethyl-1H-pyrazol-1-yl!benzenesulfonamide,mp 180°-182° C. ¹ H nmr (CDCl₃ /300 MHz) 7.97(d, J=6.6 Hz, 2H), 7.49(d,J=6.3 Hz, 2H), 7.45(d, J=6.3 Hz, 2H), 7.25(d, J=6.6 Hz, 2H), 5.78(brs,2H).

EXAMPLE 30 ##STR43## 4-1-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl!benzenesulfonamide

Step 1: Preparation ofN,N-bis(4-methoxybenzyl)-4-(aminosulfonyl)acetophenone.

To a solution of 4-(aminosulfonyl)acetophenone (2.0g, 9.0 mmol) indimethylsulfoxide (25 mL) was added NaOH (450 mg, 19.0 mmol). Thereaction mixture was stirred for 45 minutes and then 4-methoxybenzylbromide (3.5 g, 19.0 mmol) in dimethylsulfoxide (5 mL) was added viacanula. The mixture was stirred at room temperature for 24 hours andpartitioned between ethyl acetate and pH 7 buffer. The aqueous solutionwas extracted with ethyl acetate. The organic solution was dried (MgSO4)and concentrated. The residue was chromatographed on silica (2:1hexane:ethyl acetate) to give the desired product (815 mg, 21%).

Step 2: Preparation of N,N-bis(4-methoxybenzyl)-41-(4-fluorophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl!benzenesulfonamide.

Ethyl trifluoroacetate was placed in a 500 mL three-necked round bottomflask, and dissolved in methyl tert-butyl ether (75 mL). To the stirredsolution was added 25 weight % sodium methoxide via an addition funnelover a 2 minute period. Next the protected acetophenone from step 1 wasdissolved in methyl tert-butyl ether (20 mL), and added to the reactiondropwise over 5 minutes. After stirring overnight (15.75 hours), 3N HCl(70 mL) was added. The organic layer was collected, washed with brine(75 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Thesolid was recrystallized from iso-octane to give the dione.4-Flourophenyl hydrazine hydrochloride was added to a stirred solutionof the dione in ethanol (50 mL). The reaction was heated to reflux andstirred for 20 hours. After cooling to room temperature, the reactionmixture was concentrated in vacuo. The residue was taken up in ethylacetate and washed with water and brine and dried over MgSO₄, filtered,and concentrated in vacuo to give a light brown solid which wasrecrystallized from ethyl acetate and iso-octane to give the protectedpyrazole.

Step 3: Preparation of 4-1-(4-fluorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl!benzenesulfonamide.

To a solution of the protected pyrazole (50 mg, 0.08 mmol) inacetonitrile (1 mL) and water (0.3 mL) was added ceric ammonium nitrate(360 mg, 0.65 mmol). The reaction solution was kept at room temperaturefor 16 hours. The solution was poured into water (15 mL) and extractedwith ethyl acetate (2×25 mL). The combined extracts were dried (MgSO₄)and concentrated. The residue was chromatographed on silica (2:1hexane:ethyl acetate) to give the desired product (13 mg, 42%). ¹ H NMR(CD₃ OD) 7.88 (d,2H), 7.46 (d, 2H), 7.39 (dd, 2H), 7.21 (t, 2H), 7.06(s, 1H).

EXAMPLE 31 ##STR44## 4-5-(3-Fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide

Step 1: Preparation of 3'-fluoro-4'-methoxyacetophenone.

Aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL) were placedin a 2 L three-necked round bottom flask fitted with a mechanicalstirrer and cooled by means of an ice bath. To the stirred solutionacetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining thetemperature between 5°-10° C. The mixture was stirred for 10 minutes at5° C before the dropwise addition at 5°-10° C. of 2-fluoroanisole (62.6g, 0.5 mol). The mixture was stirred at 0°-10° C. for 1 hour and pouredinto ice (1 L). The resultant layers were separated and the aqueouslayer was extracted with dichloromethane (2×250 mL). The combinedorganic layers were washed with water (2×50 mL), dried over anhydrousMgSO₄, filtered and concentrated in vacuo to a volume of 300 mL. Hexaneswere added and a white solid formed which was isolated by filtration andair dried. This material was recrystallized from a mixture ofdichloromethane and hexanes to afford (77.2 g, 92%) of material suitablefor use in the next step: mp 92°-94° C.; ¹ H NMR (D₆ -DMSO) 7.8 (m, 2H),7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).

Step 2: Preparation of4,4-difluoro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione.

Ethyl difluoroacetate (4.06 g, 32.7 mmol) was placed in a 250 mLErlenmeyer flask, and dissolved in methyl t-butyl ether (50 mL). To thestirred solution was added 25 weight % sodium methoxide (7.07 g, 32.7mmol) followed by 3,-fluoro-4'-methoxyacetophenone (5.0 g, 29.7 mmol).After stirring for 16 hours, IN HCl (50 mL) was added. The organic layerwas collected and washed with water (2×50 mL), dried over anhydrousMgSO₄, filtered, and added to hexanes to precipitate a tan solid (7.0 g,96%): mp 70°-72° C.; ¹ H NMR (D₆ -DMSO)-8.0 (m, 3H), 7.3 (t, 1H), 6.9(S, 1H), 6.5 (t, 1H), 3.9 (s, 3H).

Step 3: Preparation of 4-5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol1-yl!benzenesulfonamide.

4,4-Difluoro-1-(3-fluoro-4-methoxyphenyl)butane-1,3-dione from Step 2(7.0 g, 28.4 mmol) was dissolved in ethanol (150 mL). To the stirredmixture was added 4-sulphonamidophenyl hydrazine hydrochloride (7.4 g,33 mmol) and stirred at reflux overnight (16 hours). The mixture wascooled and water was added until crystals slowly appeared. The productwas isolated by filtration and air dried to provide the desired productas a light tan solid (9.8 g, 87%) : mp 159°-161° C.; ¹ H NMR (D₆ -DMSO)7.85 d, 2H), 7.5 (m, 6H), 7.3-6.9 (m, 5H), 3.8 (s 3H). Anal. calculatedfor C₁₇ H₁₄ N₃ SO₃ F₃ : C, 51.38; H, 3.55; N, 10.57. Found: C, 51.46; H,3.52; N, 10.63.

BIOLOGICAL EVALUATION

Rat Carrageenan Foot Pad Edema Test

The carrageenan foot edema test was performed with materials, reagentsand procedures essentially as described by Winter, et al., (Proc. Soc.Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley rats wereselected in each group so that the average body weight was as close aspossible. Rats were fasted with free access to water for over sixteenhours prior to the test. The rats were dosed orally (1 mL) withcompounds suspended in vehicle containing 0.5% methylcellulose and0.025% surfactant, or with vehicle alone. One hour later a subplantarinjection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% salinewas administered and the volume of the injected foot was measured with adisplacement plethysmometer connected to a pressure transducer with adigital indicator. Three hours after the injection of the carrageenan,the volume of the foot was again measured. The average foot swelling ina group of drug-treated animals was compared with that of a group ofplacebo-treated animals and the percentage inhibition of edema wasdetermined (Otterness and Bliven, Laboratory Models for Testing NSAIDs,in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)).Results are shown in Table I.

Rat Carrageenan-induced Analgesia Test

The analgesia test using rat carrageenan was performed with materials,reagents and procedures essentially as described by Hargreaves, et al.,(Pain, 32, 77 (1988)). Male Sprague-Dawley rats were treated aspreviously described for the Carrageenan Foot Pad Edema test. Threehours after the injection of the carrageenan, the rats were placed in aspecial plexiglass container with a transparent floor having a highintensity lamp as a radiant heat source, positionable under the floor.After an initial twenty minute period, thermal stimulation was begun oneither the injected foot or on the contralateral uninjected foot. Aphotoelectric cell turned off the lamp and timer when light wasinterrupted by paw withdrawal. The time until the rat withdraws its footwas then measured. The withdrawal latency in seconds was determined forthe control and drug-treated groups, and percent inhibition of thehyperalgesic foot withdrawal determined. Results are shown in Table I.

                  TABLE I                                                         ______________________________________                                                 RAT PAW EDEMA  ANALGESIA                                                      % Inhibition   % Inhibition                                          Examples @ 10 mg/kg body weight                                                                       @ 20 mg/kg body weight                                ______________________________________                                        1        44             51                                                    1f        42*                                                                 2        39             46                                                    ______________________________________                                         *Assay performed at 20 mg/kg body weight                                 

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more compounds of Formula I inassociation with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. The compounds and composition may, for example, beadministered intravascularly, intraperitoneally, subcutaneously,intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compound that is administered andthe dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, theseverity of the disease, the route and frequency of administration, andthe particular compound employed, and thus may vary widely.

The pharmaceutical compositions may contain active ingredient in therange of about 0.1 to 2000 mg, preferably in the range of about 0.5 to500 mg and most preferably between about 1 and 100 mg. A daily dose ofabout 0.01 to 100 mg/kg body weight, preferably between about 0.1 andabout 50 mg/kg body weight and most preferably from about 1 to 20 mg/kgbody weight, may be appropriate. The daily dose can be administered inone to four doses per day.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If administered per os, the compounds may be admixedwith lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A method of treating an inflammation-associatedgastrointestinal condition in a subject, said method comprisingadministering to the subject having said condition, atherapeutically-effective amount of a compound of Formula I ##STR45##wherein R¹ is sulfamyl; wherein R² is haloalkyl;wherein R³ is selectedfrom hydrido, and alkyl; and wherein R⁴ is selected from aryl,cycloalkyl, and cycloalkenyl; wherein R⁴ is optionally substituted at asubstitutable position with one or more radicals selected from halo,alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl,alkoxycarbonyl, amido, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy,hydroxyalkyl, haloalkoxy, sulfamyl, amino, N-alkylamino,N,N-dialkylamino, heterocyclic, nitro, and acylamino; or apharmaceutically-acceptable salt thereof.
 2. The method of claim 1wherein R² is lower haloalkyl; wherein R³ is hydrido; and wherein R⁴ isselected from aryl, cycloalkyl, and cycloalkenyl; wherein R⁴ isoptionally substituted at a substitutable position with one or moreradicals selected from halo, lower alkylthio, lower alkylsulfinyl, loweralkyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl,amido, lower N-monoalkylamido, N-monoarylamido, lower N,N-dialkylamido,lower N-alkyl-N-arylamido, lower haloalkyl, hydroxyl, lower alkoxy,lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower N-alkylsulfamyl,amino, lower N-alkylamino, lower N,N-dialkylamino, heterocyclic, nitroand acylamino; or a pharmaceutically-acceptable salt thereof.
 3. Themethod of claim 2 wherein R² is selected from fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl, and dichloropropyl; wherein R³ ishydrido; and wherein R⁴ is selected from phenyl, naphthyl, biphenyl,cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl,3-cyclohexenyl, 4-cyclohexenyl, and 1-cyclopentenyl; wherein R⁴ isoptionally substituted at a substitutable position with one or moreradicals selected from fluoro, chloro, bromo, methylthio,methylsulfinyl, cyano, carboxyl, amido, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, tertbutoxycarbonyl, propoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, pentoxycarbonyl, N-methylamido, N-ethylamido,N-isopropylamido, N-propylamido, N-butylamido, N-isobutylamido,N-tert-butylamido, N-pentylamido, N-cyclohexylamido, N-cyclopentylamido,N,N-dimethylamido, N-methyl-N-ethylamido, pyrrolidinoamido,piperidinoamido, N-phenylamido, N-(3-fluorophenyl)amido,N-(4-methylphenyl)amido, N-(3-chlorophenyl)amido,N-(4-methoxyphenyl)amido, 2-pyridylamido, N-methyl-N-phenylamido,N-methyl-N-pyridylamido-, methyl, ethyl, propyl, isopropyl, tert-butyl,isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, methoxy,methylenedioxy, ethoxy, propoxy, n-butoxy, trifluoromethoxy,hydroxypropyl, hydroxyisopropyl, hydroxymethyl, hydroxyethyl, sulfamyl,methylsulfamyl, amino, nitro, methylamino, dimethylamino, formylamino,aetamino, trifluoroacetamino, and morpholino; or apharmaceutically-acceptable salt thereof.
 4. The method of claim 3wherein the compounds are selected from compounds, and theirpharmaceutically acceptable salts, of the group consisting of4-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide4-5-(3-calorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1yl!benzenesulfonamide;4-5-(4-trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4- 5-phenyl-3-(trifluoromethyl)-1H-pyrazol1-yl!-benzenesulfonamide; 4-5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4- 3-(difluoromethyl)-5-(4-methylthio!phenyl)-1H-pyrazol-1-yl!benzenesulfonamide; 4-5-(2,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol1-1-yl!benzenesulfonamide;4-5-(2,6-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4- 5-(4-biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-3-(difluoromethyl)-5-(4-(morpholino)phenyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol1-1-yl!benzenesulfonamide;4-5-(1-cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4- 3-(difluoromethyl)-5-(4-trifluoromethyl!phenyl)-1H-pyrazol-1-yl!benzenesulfonamide; 4-5-(3,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(fluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(chloromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(dichloromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(dichlorofluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2,4,6-trifluorophenyl)-3-(trifluoromethyl))-1H-pyrazol1-yl!benzenesulfonamide;4-5-(2,6-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2,4,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol1-yl!benzenesulfonamide;4-5-(2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3,4-dimethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3,4-methylenedioxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-fluoro-4-methoxypbenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-fluoro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-benzenesulfonamide;4-5-(2-methythiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3-methythiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-methythiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-fluoro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-chloro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chloro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3,4-dihydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4- 5-(biphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-ethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(6-methoxy-2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-N-ethylaminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-N,N-dimethylaminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-N-formylaminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-N-acetaminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-N-methylsulfonamidophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-hydroxymethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(cyclohexyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(cyclopentyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(cycloheptyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(1-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;and 4-5-(1-cyclopentenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide.5. The method of claim 1 wherein R¹ is sulfamyl; wherein R² is lowerhaloalkyl; wherein R³ is lower alkyl; and wherein R⁴ is selected fromaryl, cycloalkyl, and cycloalkenyl; wherein R⁴ is optionally substitutedat a substitutable position with one or more radicals selected fromhalo, lower alkylthio, lower alkylsulfinyl, lower alkyl, loweralkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, amido, lowerN-monoalkylamido, N-monoarylamido, lower N,N-dialkylamido, lowerN-alkyl-N-arylamido, lower haloalkyl, hydroxyl, lower alkoxy, lowerhydroxyalkyl, lower haloalkoxy, sulfamyl, lower N-alkylsulfamyl, amino,lower N-alkylamino, lower N,N-dialkylamino, heterocyclic, nitro andacylamino; or a pharmaceutically-acceptable salt thereof.
 6. The methodof claim 5 wherein R² is lower haloalkyl; wherein R³ is lower alkyl; andwherein R⁴ is aryl optionally substituted at a substitutable positionwith one or more halo radicals; or a pharmaceutically-acceptable saltthereof.
 7. The method of claim 6 wherein R² is selected fromfluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl; wherein R³ is selectedfrom methyl, ethyl, propyl, isopropyl, and butyl; and wherein R⁴ isphenyl optionally substituted at a substitutable position with one ormore radicals selected from fluoro, chloro and bromo; or apharmaceutically-acceptable salt thereof.
 8. The method of claim 7wherein the compounds are selected from compounds, and theirpharmaceutically acceptable salts, of the group consisting of4-5-(4-chlorophenyl)-3-(trifluoromethyl)-4-methyl-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-fluorophenyl)-3-(trifluoromethyl)-4-propyl-l1H-pyrazol-1-yl!benzenesulfonamide;and 4-5-(4-fluorophenyl)-3-(trifluoromethyl)-4-methyl-1H-pyrazol1-yl!benzenesulfonamide.9. A method of treating an inflammation-associated gastrointestinalcondition in a subject, said method comprising administering to thesubject having said condition, a therapeutically-effective amount of acompound of Formula II ##STR46## wherein R² is lower haloalkyl; whereinR³ is hydrido; andwherein R⁴ is selected from aryl, cycloalkyl, andcycloalkenyl; wherein R⁴ is optionally substituted at a substitutableposition with one or more radicals selected from halo, lower alkylthio,lower alkylsulfonyl, cyano, lower haloalkyl, lower alkyl, hydrido, loweralkoxy, lower haloalkoxy, sulfamyl, heterocyclic and amino; or apharmaceutically-acceptable salt thereof.
 10. The method of claim 9wherein R² is selected from fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, anddichloropropyl; wherein R³ is hydrido; and wherein R⁴ is selected fromphenyl, biphenyl, cyclohexyl, and cyclohexenyl; wherein R⁴ is optionallysubstituted at a substitutable position with one or more radicalsselected from fluoro, chloro, bromo, methylthio, methylsulfonyl,morpholino, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy,fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl, and dichloropropyl; or apharmaceutically-acceptable salt thereof.
 11. The method of claim 10wherein the compounds are selected from compounds, and theirpharmaceutically acceptable salts, of the group consisting of4-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4- 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide; 4-5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4- 5-(4-methylthio!phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide,4-5-(2,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(2,6-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-heptafluoropropyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol1-yl!benzenesulfonamide;4-5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4- 5-(4-biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(4-(morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1yl!benzenesulfonamide;4-5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(1-cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1yl!benzenesulfonamide;4- 5-(4-trifluoromethylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide;4-5-(3,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1yl!benzenesulfonamide;and 4-5-(2,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1yl!benzenesulfonamide.12.The method of claim 10 where the compound is 4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
 13. The method ofclaim 10 where the compound is 4-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
 14. The method ofclaim 10 where the compound is 4-5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl!benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
 15. Themethod of claim 1 wherein the condition is selected from as inflammatorybowel disease, Crohn's disease, gastritis, irritable bowel syndrome andulcerative colitis.
 16. The method of claim 15 wherein the condition isinflammatory bowel disease.
 17. The method of claim 15 wherein thecondition is irritable bowel syndrome.
 18. The method of claim 15wherein the condition is ulcerative colitis.